chalcone review

Expert Opinion on Drug Discovery
ISSN: 1746-0441 (Print) 1746-045X (Online) Journal homepage: https://www.tandfonline.com/loi/iedc20
Recent developments in biological aspects of

chalcones: the odyssey continues
Anu Rani, Amit Anand, Kewal Kumar & Vipan Kumar
To cite this article: Anu Rani, Amit Anand, Kewal Kumar & Vipan Kumar (2019) Recent
developments in biological aspects of chalcones: the odyssey continues, Expert Opinion on Drug
Discovery, 14:3, 249-288, DOI: 10.1080/17460441.2019.1573812
To link to this article: https://doi.org/10.1080/17460441.2019.1573812
Published online: 18 Feb 2019.
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EXPERT OPINION ON DRUG DISCOVERY
2019, VOL. 14, NO. 3, 249–288
https://doi.org/10.1080/17460441.2019.1573812
REVIEW
Recent developments in biological aspects of chalcones: the odyssey continues

Anu Rania, Amit Anandb, Kewal Kumarc and Vipan Kumara
a
Department of Chemistry, Guru Nanak Dev University, Amritsar, India; bDepartment of Chemistry, Khalsa College, Amritsar, India; cDepartment of
Applied Chemistry, Maharaja Ranjit Singh Punjab Technical University, Bathinda, India
ABSTRACT ARTICLE HISTORY

Introduction: Chalcones are attractive to synthetic chemists because they are easy to prepare, have Received 7 November 2018
a large number of replaceable hydrogens, thereby having significant biological potential. Chalcones Accepted 21 January 2019
and their derivatives (carbocyclic as well as heterocyclic) exhibit a range of biological properties KEYWORDS
including anticancer, antimalarial, antioxidant, anti-inflammatory and anti-tubercular activities. Their Claisen-schmidt
promising biological profile, along with their ease of synthetic manipulations, have triggered the design condensation; chalcones;
and development of new chalcone derivatives as well as their conjugates with active pharmacophores Structutre Activity
affording therapeutic templates targeting various diseases. Relationship (SAR);
Areas covered: This review focuses on synthesized substituted chalcones as well as chalcone-based anti-proliferatives; anti-
molecular conjugates that have been developed between 2015 and 2018. Furthermore, their structure– oxidant; anti-malarial
activity relationships with an emphasis on their mechanism of action and docking studies along with
their future therapeutic applications.
Expert opinion: A recent upsurge in scientific literature encompassing the synthesis of new chalcone-
derivatives as well as its role in ameliorating the activity profiles via amalgamation with other pharma-
cophores has clearly established the importance of chalcones in present-day drug discovery. As a point,
we, the authors, believe that new effective scaffolds can be developed from chalcones with an added
advantage of being available at a low cost.
1. Introduction scientific reports appeared lately (2015–18) on the synthesis

and biological potential of variedly functionalized chalcones.
1,3-diaryl-prop-2-en-1-ones, popularly known as chalcones are
Emphasis would be given towards the Structure–Activity
important core-structures belonging to the flavonoid family
Relationship (SAR) of the synthesized scaffolds as well as the
and act as synthetic precursors to various flavonoids and
enzymatic studies of the promising molecules.
isoflavonoids [1]. Of the various forms they exist in nature,
the molecular framework of chalcone includes the presence of
aryl rings connected through a three carbon viz. α, β- 2. Biological activities
unsaturated carbonyl chain (Figure 1) [2]. Chalcones, thus
2.1. Chalcones as anti-cancer agents: synthesis and
can exist in two isomeric forms viz. Z and E of which the
biological evaluation
E-isomer is considered as thermodynamically favorable [3].
The occurrence of chalcones in nature can be as they acknowl- Cancer is a life-threatening disease characterized by uncon-
edged are considered to be responsible for floral coloration, trolled progression and metastasis of unusual or inconsistent
imparting yellow/red pigmentation because of their highly cells [13–16]. The American Cancer Society estimated over
conjugated structures, thus attracting insects like bees and 1,735,350 new cancer cases and over 609,640 deaths in the
butterflies for pollination. Plants like Angelica keiskei, US alone in 2018 [17,18]. In spite of preferred method, che-
Glycyrrhiza inflate and Piper aduncum are rich source of chal- motherapy is still considered inadequate providing a strong
cones and have been used extensively by the natives for their impetus for new molecular frameworks with a low incidence
medicinal potential [2,4]. Besides, chalcones, because of their of resistance [19–21]. Due to the relative ease of preparation,
ease of synthesis, large number of replaceable hydrogens as structural diversity and facile chemical manipulation, many
well as ease of synthetic manipulations, have attracted the chalcones of natural and synthetic origin have been recognized
attention of organic medicinal chemists worldwide. for modulating important therapeutic pathways or molecular
A large number of research publications dedicated to the targets in cancer [22–24]. In addition, the literary rationale
synthesis and bio-activities of chalcones appear every year revealed strategies viz. structural manipulation of aryl rings,
specifically exploring their antioxidant [5], anticancer [6,7], replacement of aryl rings with heteroaryl/ferrocenyl core as
anti-tubercular [8], anti-inflammatory [6,9], antimalarial [10], well as conjugation with other pharmacologically active scaf-
antifungal and antiviral activities [11,12]. The aim of the pre- folds for enhancement of anticancer properties of chalcones
sent review article is to take the readers on an odyssey of [25–33]. These strategies have enabled the development of new
CONTACT Vipan Kumar vipan_org@yahoo.com Department of Chemistry, Guru Nanak Dev University, Amritsar 143005, India
© 2019 Informa UK Limited, trading as Taylor & Francis Group
250 A. RANI ET AL.
chalcone-based scaffolds with potential therapeutic applica-

Article highlights tions in various cancers.
● Chalcones or the α, β-unsaturated ketones, are open chain flavonoids
A series of β-carboline-chalcone conjugates 6 were synthe-
that act as biogenetic precursors of flavonoids in higher plants. sized from 1-acetyl- β-carboline 3 and different aldehydes 4
● Claisen-Schmidt condensation is mainly employed for affording followed by N2-alkylation with varied alkyl bromides by Reddy
chalcones.
● The unique α,β-unsaturated ketone core of chalcone is responsible
et al (Scheme 1) [13]. The synthesized scaffolds were in vitro
for the broad-spectrum of biological activities exhibited by this evaluated for cytotoxicity against a panel of cancer cell lines
molecule. viz. pancreatic (BxPC-3), cervical (HeLa), castration-resistant
● Chalcones and its derivatives have received considerable attention
due to their anticancer, antibacterial, antifungal, antimalarial, antiox-
prostate (C4-2), human prostate (PC-3), human embryonic
idant, anti-inflammatory and antitubercular activities. kidney 293 (HEK293T) and breast carcinoma (MDA-MB-231)
● Anticancer activity of chalcones could be attributed via induction of cells. The presence of substituents on β-carboline (-R) and
apoptosis, blockage cell cycle progression in the G2/M phase and
inhibition of tubulin polymerization.
aryl (-Ar) ring affected the activity profiles with IC50s ranging
● Chalcones have also exhibited promising antimalarial potential from 15.9 to >100 µM. Compound with H-as substituent on β-
because of their ability to inhibit cysteine/aspartic proteases. carboline and enone showed moderate anticancer activities
This box summarizes key points contained in the article. with IC50s in the range of 65.5–93.0 µM. Loss of activity was
observed with the introduction of methyl, 4-OCH3 as well as
3,4-di-OCH3 groups on the aryl ring of enone. N2-Alkylated-β-
carboline-chalcones 6 displayed improved anticancer proper-
ties compared to unsubstituted analogs 5. The presence of
benzyl at N2 afforded compounds having moderate activity
(IC50 = 15–88 µM). Conspicuously, compound 7 was the most
potent scaffold of the series against all the tested cell lines
(IC50 = 15.9–22.1 µM). N2-butylated analogs displayed inferior
Figure 1. Structure of chalcone. activities (IC50 = 25.1->100 µM) compared to benzylated
Scheme 1. Synthesis of β-carboline-chalcones and their bromide salts. Reagents and conditions: (a) Pyruvaldehyde, TFA, DCM, 30°C, N2, 48 h, (b) 10% Pd/C, Xylene,
reflux, 24 h (c) Di-tert-butyldicarbonate, THF, DMAP, 24 h (d) 20% NaOH, 50% ethanol-water, 0 °C-25°C, 16 h (e) RBr, DMF, 50°C, 12 h [34].
EXPERT OPINION ON DRUG DISCOVERY 251
analogs. Further, the presence of benzyl group evidently Furthermore, the presence of functionality, a hydroxyl at
prompted cell death in MDA-MB-231 (IC50 = 15.95 µM) cells. C-14 showed moderate activity (IC50 = 42 µg/mL) while the
All the synthesized compounds were low cytotoxic than presence of a hydroxyl group at C-16 substantially decreased
Doxorubicin [34]. the activity (IC50˃50 µg/mL). Further, the sensitivity of most
Trisubstituted imidazo[1,2-a]pyridines 9 were synthesized, active compound against normal fibroblasts cell line was com-
and engrossed into corresponding chalcones 10 by Kuthyala pared revealing it is several folds less sensitive (NHLF IC50
et al. (Scheme 2) [14] All the compounds were screened = 122 µg/mL) compared to cancer cell line [35].
against A549 cell line using MTT assay, and the compounds Nitro-aminochalcones (NAC) 14 were synthesized and evalu-
exhibited IC50 in the range of 7–42 µg/mL. The validation of ated for its anti-tumor properties against human glioblastoma,
the potent compounds was done by docking into the protein breast, colon, and leukemia cell lines by Michelini et al using the
complex (4ph9). Furthermore, their hemocompatibility was tetrazolium3-(4,5-dimethyl-2-thiazole)-2,5-diphenyl-
analyzed by in vitro hemolytic assay. The derivatives 11 bear- 2-H-tetrazolium bromide (MTT) assay (Scheme 3).
ing methyl substitutent on ring-A and nitro at C-15 showed Nitroaminochalcones (NAC) 14 displayed high anti-proliferative
excellent activity against A549 cell line (IC50 = 7.0 µg/mL). activities at a concentration of 93.2 µmol/L. The synthesized
chalcones had the lowest IC50 among the series against the PC-
3 cell line. NAC exhibited lesser IC50s than Doxorubicin (543.52 g/
mol); the positive control against the tested cancer cell lines [36].
Wang and co-workers have synthesized, characterized and
evaluated a series of naphthalene-chalcones 18 for in vitro
antiproliferative activity against HCT116 and HepG2 cells
using MTT assay, using millepachine as the reference standard
(Scheme 4). The activity results showed that most of the
screened scaffolds have potent anti-proliferative activity
against HCT116 and HepG2 cancer cell lines. Analyzing the
SAR indicated the improvement in anti-proliferative activity
with the induction of electron-withdrawing substituents viz. -
Cl and – Br at C-3 of the phenyl ring. Changing the position of
these group to C-2 or C-4 reduced the antiproliferative effi-
Scheme 2. Synthesis of trisubstituted imidazo[1,2-a]pyridine derivatives.
Reagents and conditions: (a) 3-chloro-2,4-pentadione, DCM, reflux, 4 h (b) cacy. Additionally, the presence of – OCH3 at C-4 position
Ethanol, 40% NaOH, RT, 24 h [35]. improved the anticancer activities. A decrease in activity was
evident by replacing a 4-methoxy with a 2-methoxy substitu-
ent. The inhibitory activity results have shown the influence of
substituents present on the naphthalene ring on the antic-
ancer activity. Compound 19 having a diethylamine substitu-
ent at C-4 position proved to be the most potent with IC50s of
1.20 and 1.02 µM against HCT116 and HepG2 cell lines, respec-
tively. Tubulin polymerization was done in order to examine
the interaction of the promising compound 19 with tubulin
using Colchicine as the reference. 19 and colchicine inhibited
Scheme 3. Reactional scheme of NAC synthesis [36]. the polymerization of tubulin in a concentration-dependent
Scheme 4. Synthesis of naphthalene-chalcone derivatives. Reagents and conditions: (a) AlCl3, Acetyl chloride, CH2Cl2, 0 °C, 30 min to RT, overnight (b) KOH, CH3OH,
RT, 48 h [37].
252 A. RANI ET AL.
23 against human Raji B-cell lymphoma, human JeKo-1 mantle

cell lymphoma as well as U937 was compared with doxorubi-
cin and cisplatin. The cytotoxicity of 23 against lymphoma
cells was better than cisplatin, but less than doxorubicin [38].
Wang et al. have synthesized, characterized and evaluated
a series of aminochalcone derivatives 26, 27 for their anti-
proliferative activity against a panel of cancer cell lines using
MTT assay (Scheme 6). Moderate to potent anti-proliferative
activities was observed against tested cancer cell lines with
scaffold 26 exhibiting IC50 values ranging from 0.018 to
5.33 µM. In particular, 26 exhibited IC50 values of 0.28 ± 0.06
and 0.19 ± 0.04 µM against HepG2 and HCT116 cells, respec-
tively. SAR studies revealed a decrease in anti-proliferative
activity via induction of alkyl substituents (alkyl/acyl) on free
Scheme 5. Synthesis of diverse indolizine-chalcone conjugates [38].
amine. The most promising compound of the series, 26 was
selected for its ability to inhibit tubulin polymerization. 26 and
reference compound, colchicine suppressed in vitro tubulin
mode with 19 displaying IC50 of 22 µM compared to colchicine polymerization in a dose-dependent manner [39].
(IC50 = 9 µM). 19 also arrested HepG2 cells at G2/M phase in 4-amino-5-cinnamoylthiazoles 33 were designed, synthe-
a dose-dependent manner [37]. sized and evaluated for their antiproliferative activities against
Park and co-workers have reported a series of indolizine- a panel of cancer cell lines by Ayati and co-
chalcone hybrids 22 obtained via base-promoted aldol con- workers (Scheme 7). The nature of cyclic amine at C-2 position
densation of indolizine 20 with various aromatic (hetero) alde- along with substituents on aryl ring was varied so as to
hydes 21 (Scheme 5). Biological evaluation revealed that establish the SAR studies. In particular, 34 having a pyrrolidine
among the compounds tested, 23 with 3,5-dimethoxyphenyl ring exhibited promising activity against HepG2 cells with IC50
as substituent proved to be most active and inhibited the value of 10.6 µg/mL, being two folds potency than piperidine
viability of human lymphoma U932 cells. Among halogen and morpholine analogs. The un-substituted cinnamoyl deri-
substituents, the meta-position seemed to be preferred for vatives (R = H) proved to be active against the tested cell lines.
good activity than the para-position. In addition, the cas- An increase in cytotoxicity was observed in pyrrolidine-series
pase-3/7 activity assay and analysis of Annexin V-positive with the introduction of chloro substituents at C-2 and C-4
cells revealed that the compound 22 induced death of U937 position. The replacement of -Cl with -Br had an adverse effect
cells due to caspase-dependent apoptosis. The cytotoxicity of on the activity against SW480 cell line, exception being
Scheme 6. Synthesis of aminochalcone derivatives. (a) KOH, CH3OH, RT, 48 h (b) Fe, NH4Cl, CH3CH2OH/H2O (3:1, v/v), 80°C, 3 h (c) K2CO3, R1/R2X, CH3CN, reflux, 12 h
and R1COCl, Et3N, CH2Cl2, RT 12 h [39].
Scheme 7. Synthesis of chalcones. Reagents and conditions: (a) (i) cyclic amines 29, DMF, 70°C, 1 h (ii) Na2S·9H2O 60%, 70°C, 90 min (iii) chloroacetone, 50°C, 2 h (b)
K2CO3, 50°C, 1 h (c) 10% NaOH, methanol, 0–5 °C [40].
Scheme 8. Synthesis of pyridyl-indole based chalcones. Reagents and conditions (a) Piperidine, methanol, reflux 80°C, 16 h (b) Sulfonyl chlorides, Na2CO3, 50%
THF:H2O, RT, 24–48 h [41].
pyrrolidine and morpholine substituted analogs. Flow cyto- assay with Doxorubicin was used as a positive control.
metric studies showed that the compound 34 could inhibit Interestingly, all compounds hindered the viability of cells
HepG2 cell proliferation via obstruction of G2 phase [40]. with compound 39 being most prominent among series
Peerzada and co-workers have reported pyridyl-indole with IC50 value of 12.2 µM. In case of HEK-293 cells, the
chalcones 38, obtained via Knoevenagel condensation tested compounds proved to be in-effective in inhibiting
between 4-acetylpyridine 35 and indole-3-carbaldehyde the proliferation of HEK-293 cells [41].
36, as effective carbonic anhydrase (CA) inhibitors. The Pontes et al. have reported the synthesis of chalcone 42
reaction of synthesized chalcones 37 with various sulfonyl and chromene 43 derivatives using safe solvents such as water
chlorides afforded the corresponding sulphonamides and ethanol at room temperature (Scheme 9) along with
(Scheme 8). Enzyme inhibition activities of synthesized evaluation on breast cancer (MCF-7 and Hs578T) and non-
compounds were carried out against carbonic anhydrase neoplastic cells (MCF-10A). SAR analysis revealed that scaffolds
using acetazolamide as a reference. The compound 39 having halogen substituents exhibited better anti-proliferative
proved to be more active with IC50 of 0.13 µM. activities compared to methoxy (-OCH3) or methyl (-CH3)
Compounds having electron withdrawing – NO2 or elec- groups with chalcones displaying lower IC50s compared to
tron-donating tert-butyl substituent displayed similar IC50 chromenes, on both cancer cell lines. Compounds 44 and 45
values of 0.15 µM. Further, anti-proliferative activities on proved to be most promising because of their less aggressive
MCF-7 and HepG-2 cells was carried out using the MTT effect on MCF-10A and better selectivity index [42].
254 A. RANI ET AL.
Scheme 9. Synthetic pathway for the synthesis of chalcones chromenes. Reagents and condition: (a) EtOH, NaOH, 3M, RT or 40–60°C (b) Et3N, MeOH or EtOH, RT [42].
Scheme 10. Synthesis of the Pt(IV) complexes. Reagents and conditions: (a) 50% KOH/H2O, methanol, 0 °C (b) Fe, NH4Cl, EtOH, 85°C (c) EDCI, DMAP, CH2Cl2, RT (d)
LiOH.H2O, THF/H2O, RT (e) TBTU, Et3N, DMF, RT [43].
Six Pt(IV) derived pro-drugs 53–55 obtained from Cisplatin resistance with low resistance indices. The promising com-
(CDDP), dichloro(1R,2R-diaminocyclohexane)platinum(II) pounds viz. 53a-b were chosen for further biological studies
(DACHPt) and oxaliplatin (OXP) along with chalcone analogs and were 2.71- and 5.54-folds cytotoxic on SK-OV-3 cells than
52a-b were synthesized and evaluated against three human 52. 53a and 53b also exhibited higher sensitivity against
cancer and two human normal cell lines by Huang and co- HepG-2 and NCI-H460 cancer cells with IC50 values of 2.23,
workers (Scheme 10). In vitro evaluation showed the Pt(IV) 4.65 and 0.97, 3.66 µM. All Pt(IV) complexes displayed lower
complexes to be less cytotoxic and has better antiprolifera- cytotoxicity than corresponding Pt(II) positive controls
tive activities than Pt(II) counterparts. In addition, Pt(IV) com- (CDDP, DACHPt and OXP) suggestive of the fact that Pt(IV)
plexes exhibited competence to over-come CDDP drug complexes displayed better selectivity. Tubulin
Scheme 11. Synthesis of 1H-1,2,3-triazole-tethered Isatin-ferrocene conjugates 61. Reagents and conditions: (a) Me-I or benzylbromide, Dry DMF, NaH, 1h, RT (b)
TMSI, NaH, Dry DMF, 0° – RT, 30 min (c) EtOH:H2O, 1h, NaN3, RT (c) CuSO4.5H2O, Sodium ascorbate EtOH:H2O [44].
Scheme 12. Synthesis of 1H-1,2,3-triazole-linked isatin-ferrocenylchalcone conjugates 66 [44].
Scheme 13. Synthesis of mono Mannich bases of 2-(4-hydroxybenzylidene)-2,3-dihydroinden-1-one J1-3. Reagents and conditions: (a) Dry HCl, MeOH, RT (b) CH3CN,
13.8 barr, 150 Watt, 5 min, 80°C [45].
256 A. RANI ET AL.
Scheme 14. Synthesis of the compounds 73. Reagents and conditions (a) MeOH, 40% aq. KOH, reflux, 3 h, 70°C [46].
polymerization assay and molecular docking studies further HSC-4) and three human normal oral cells (HGF, HPLF, and HPC)
indicated that complexes 53a and 53b could inhibit tubulin by MTT test. Doxorubicin was used as the reference drug. The
polymerization and bind to the colchicine site of tubulin [43]. CC50 values of the compounds were in the range of 0.9–109.8 µM
Kumar and co-workers have synthesized a series of isatin- towards OSCC malign cell. All the compounds showed high
ferrocene 61 and isatin-ferrocenylchalcone 66 conjugates via Selectivity Index (SI) values in the range of 1.8–76.5. The com-
Cu-promoted click-chemistry along with anti-proliferative eva- pound 74 bearing 2,4,5-trimethoxyphenyl core had the highest
luation against MCF-7 (estrogen receptor positive) and MDA- selectivity value (SI = 76.5), which was 1.6 times more than
MB-231 (triple negative) cell lines (Scheme 11 and 12). Among reference drug doxorubicin and highest potency-selectivity
the synthesized conjugates, isatin-ferrocenes 61 proved to be expression (PSE = >1285, > 1602) value (Scheme 14). Western
more potent against MCF-7 cell line. However, the introduc- blot analysis proposed that 74 (8–64 μM) induced apoptosis in
tion of chalcone moiety among these hydrids resulted in the HSC-2 cells and showed highest tumor specificity (TS = >63.2),
complete loss of activity against the tested cell lines as evident being superior than that of doxorubicin (TS = 39.0). Quantitative
by isatin-ferrocenylchalcones 66. The conjugate N-benzyl isa- Structure–Activity Relationship QSAR analysis suggested that
tin-ferrocenylchalcone 67 proved to be most potent among molecular shape, volume, and electrostatic properties were
the isatin-ferrocenylchalcones series against MCF-7 cell line important factors to increase the tumor specificity of the chal-
exhibiting IC50 values of 55.70 µM [44]. cones in addition to the location of substituted groups [46].
Badr et al. investigated the anti-tumor potential of three Williams and co-workers prepared a library of pyrrole-based
curcumin analogs J1, J2, and J3, understanding the under- chalcones 77 under the given reaction conditions as depicted
lying molecular mechanisms in the human breast carcinoma in Scheme 15. Twenty three aryl substituents were varied and
cell lines, MDA-MB-231 and MCF-7 using the MTT assay along the compounds were assayed for their anticancer activities by
with cytotoxicity on non-tumorigenic normal breast epithelial inhibiting CYP1 isoforms. Activity data demonstrated that
cells (MCF-10). Curcumin analog J1 inhibited the growth of many of synthesized chalcones inhibited various isoforms
MDA-MB-231 and MCF-7, but not of MCF-10 cells, in a dose
and time-dependent manner. Curcumin analog J1 exerted,
in vitro inhibitory effects against proliferation of MDA-MB-231
and MCF-7 cells by significantly (P < 0.05) diminishing mito-
chondrial membrane potential and subsequently increased
the percentages of apoptotic cells to 75% and 79%, respec-
tively. The anticancer effect of J1 was mediated through PI3k/
AKT/mTOR signaling pathway. Moreover, curcumin analog J1
inhibited actin polymerization via eliminating the activation of
the RhoA/ROCK pathway. J1 had no significant inhibitory
effect on the viability of non-tumorigenic normal breast
epithelial MCF-10 cells. However, curcumin analogs J2 and
J3 showed cytotoxic effects on both breast cancer cells (MDA-
MB-231 and MCF-7) and also the non-tumorigenic normal
breast epithelial (MCF-10) cells (Scheme 13) [45].
Gul and co-workers reported the cytotoxicity, apoptosis, and
QSAR studies of phenothiazine derived methoxylated chalcones Scheme 15. Synthesis of pyrrole based chalcones 77. Reagents and conditions:
73. Cytotoxicities were evaluated against four human oral squa- (a) 5-equivalents NaOH/KOH grinding using mortar and pestle [47].
mous cell carcinoma (OSCC) cell lines (Ca9-22, HSC-2, HSC-3, and
and the results were compared with control α-napthoflavone cells remained unaffected. Antiproliferative effects were com-
(AFN). Chalcone 78 was found to be the most prominent pared with the standards shikonin and colchicines. All the
compound with an IC50 value of 0.9 µM against both compounds exhibited IC50 values in the range of 2.36 to
CYP1A1 and CYP1B1 enzymes. Almost all the chalcones were 20.66 µM against the three cancer cell lines used. The com-
active against isoform 1A2 with the most potent compound pound 93 was the most potent compound among the series
79 having IC50 value of 0.7 µM. All the chalcones displayed with IC50 value of 4.53 (HeLa), 2.36 (MCF-7), 5.84 (A549) and
good activity with IC50 values ranging from range 11–20 µM, safe to noncancerous cells [49].
while the control exhibited an IC50 value of >20 µM. These Yamali and co-workers has synthesized a series of difluor-
compounds were unable to inhibit the isoforms 2C9, 2C19 and odimethoxylated chalcones as depicted in Scheme 18 and
3A4 as IC50 values against these enzymes were found to be evaluated their in vitro cytotoxic effects against human
>20 µM. Chalcones 78 and 79 were most efficient against tumor cell lines [gingival carcinoma (Ca9-22), oral squamous
most of the isoforms used for testing. These compounds cell carcinoma (HSC-2)] and human normal oral cells [gingival
were then utilized for the inhibition in live HEK293 cells. Live fibroblasts (HGF), periodontal ligament fibroblasts (HPLF)] via
cell results clearly supported enzymatic activity results as both MTT test. Except for 3,4-methoxy chalcone, all compounds had
the compounds inhibited the 1B1 and 1B2 live cells with IC50 2.1–9.7 times higher cytotoxicity toward Ca9-22 and 1.1–11.4
values of 1.2 and 1.1 µM, respectively, [47]. folds towards HSC-2 cell line than the reference compound,
Ren and co-workers have reported the synthesis and antic- 5-FU. SI values were in the range of 4.5–21.2 towards Ca9-22
ervical cancer activity of a library of chalcones 82, 85 prepared cells while it was in the range of 4.0–23.7 towards HSC-2 cell
under different reaction conditions as shown in Scheme 16 line. The compound with the highest PSE value (442) was the
and evaluated for their antiproliferative activities against compound 97, [1-(3,5-difluorophenyl)-3-(2,5-dimethoxyphe-
human cervical cancer cell lines namely HeLa and SiHa. nyl)-2-propen-1-one and had apoptosis-inducing activity
Anticancer activity results against both the cell lines revealed against human oral squamous cell carcinoma [50].
that almost all the chalcones inhibited the cancer cells effec- Lima et al. reported terpenoid-like chalcones 101, 102 via
tively. The activity values lie in the range of 0.082–63.72 µM Claisen–Schmidt condensation reaction, using either α-or β-
except for chalcones with no substitution at ring A and B. The ionone 98, 99 with substituted benzaldehydes 100 (Scheme 19).
structures of the most potent compounds 86 and 87 having The synthesized compounds were tested for their cytotoxic activ-
IC50 values less than 1.0 µM is shown in Scheme 16 which ity against three cancer cell lines viz SF-295, HCT-116, and OVCAR-
exhibited an IC50 of 0.082 and 0.035 µM, respectively, against 8, for establishing structure–activity relationship. Chalcones with
HeLa cell lines. Further, these chalcones were found more nitro substituted phenyl rings, regardless of its position and
potent against SiHa cancer cell lines after 72 h compared to ionone type, were the most active among all that tested com-
HeLa. The SAR studies also suggested that the nitro and pounds revealing that the presence of one nitro moiety is decisive
dimethylamine as a substituent at ring B of the chalcone for cytotoxicity of the terpenoid-like chalcones. The decrease in
resulted in the enhancement in anticancer activity profiles cytotoxic activity with the introduction of weak electron-
against both the cell lines used [48]. withdrawing groups like nitro, bromo at phenyl ring was also
Qiu and co-workers reported the synthesis (Scheme 17) and supported on the basis of their IC50 values. Most potent of tested
anticancer activity of Chalcone-containing shikonin derivatives compound 103 having a nitro substituent at ortho position exhib-
92 against HeLa, MCF-7 and A549 human cancer cell lines as ited an IC50 value of 2.70 µmol/L against HCT-116 [51].
well as L02 and 293T noncancerous cell lines. All the reported Synthesis and anti-cancer screening of a series of substi-
compounds inhibited the cancer cells while noncancerous tuted chalcones and their complexes with [Ru(II)(DMSO)4Cl2]
Scheme 16. Synthesis of variedly substituted chalcones [48].

258 A. RANI ET AL.
Scheme 17. Synthesis of chalcone-containing shikonin derivatives. Reagents and conditions: (a) acetophenone, NaOH, 0°C, 2h; (b) NaOH, EtOH, 90°C, 6h; (c) DCC,
DMAP, CH2Cl2, 0°C, 1h [49].
Scheme 18. General procedure for the synthesis of the chalcones 96. Reagents and conditions: (a) EtOH, NaOH solution (30%), RT [50].
Scheme 19. Terpenoid like chalcones [51].

against breast cancer cell lines (MCF-7 and MDA MB-231) and nuclear changes, DNA fragmentation and cell cycle arrest
using MTT assay was recently reported by Singh et al. in breast cancer cells. Compound HL4 showed IC50 value of
Compounds HL4 and MR-a showed significant anti-breast 18.5 µM against MDA MB-231 while complex MR-a showed an
cancer activity as evident from cytotoxicity, morphological IC50 of 15 µM and 28.64 µM against MCF-7 and MDA MB-231
Scheme 20. Synthesis of Ru(II) complexes with substituted chalcones [52].
Scheme 21. Synthesis of chalcone hybrid derivatives. Reagents and conditions: (a) 20%, KOH, EtOH, rt, 24 h (b) piperazine hexahydrate, Cs2CO3, DMF, 110°C, 12 h (c)
RCOCl, Et3N, DCM, 0°C, 2 h (d) RCOOH, DCC, DMAP, DCM, 24h; (e) RSO2Cl, Pyridine, DCM, RT, 12 h (f) Cs2CO3, 2-bromoacetophenone, DCM, RT, 4h [53].
Scheme 22. Synthesis of piperidinyl chalcones analogues 119. Reagents: (a) Hydrochloric acid, Glacial acetic acid, RT, 24 h, 95–100°C, 3 h. (b) Boron triflouride
ethereate, acetic anhydride, dichloromethane, RT, 24–72 h. (c) 10% w/v sodium hydroxide, methanol, RT, 12–24 h [54].
260 A. RANI ET AL.
cell lines, respectively (Scheme 20). The improvement in antic- to be the lead molecules for further anticancer drug candidate
ancer activity has been clearly established in Ru(II) complexes developments. The compounds evaluated for carbonic anhy-
of these chalcones [52]. drase enzyme inhibitory effects showed a low inhibition
A series of chalcone (108–112) having substituted pipera- potency toward hCA I (25–43%) and hCA II (6–25%) isoforms
zine ring has been synthesized by Mao et al. and assayed for at 10 µM concentration [55].
their antitumor activities (Scheme 21). The presence of halo- Banday and co-workers have reported a series of epipodo-
gen substituent at p-position proved to be important for phyllotoxin–chalcone hybrids obtained via click-chemistry as
modulating cytotoxicity. Among all the compounds synthe- topoisomerase-II inhibitors (Scheme 24). The anti-proliferative
sized, compound 113 with a p-chloro-substituent proved to evaluation of synthesized conjugates against cancer cell lines
be the most active [53]. confirmed non-chalconated analogs to be less active than the
Jayashree et al. has reported the synthesis of a variety of chalconated hybrids. Further, 4’-O-demethyl analogs have
chalcones 119 having tetrahydropiperidinyl functionality and shown better activity than the corresponding methylated
evaluated their in vitro antioxidant and anticancer activity ones. Among all the compounds evaluated, compound 129
(Scheme 22). The synthesized scaffolds exhibited significant with a fluorinated chalcone exhibited the highest cytotoxicity
anticancer activity against A549, HepG2, HeLa, HCT-116, MCF-7 and selectively against SW-620 (0.35 µM) and SKN-SH (0.39µM)
and MDA MB 231 cancer cells. Further, the test compounds cell lines. Further, the energy calculations obtained from dock-
having naphthalene core exhibited antioxidant activity in vitro ing studies against topoisomerase-II were in good agreement
as confirmed via 2,2’-azino-bis(3-ethylbenzothiazoline-6-sulfo- with the observed IC50 values [56].
nic acid) (ABTS) radical cation, superoxide radical scavenging, L. Wang et al. synthesized a series of chalcone derivatives 136
o-phenonthroline, and lipid peroxidation assays. The antican- and their biological activities against HIF-1 (hypoxia inducible
cer activity of the promising compounds was attributed for factor) were evaluated (Scheme 25). HIF-1 has been identified as
their ability to induce apoptosis, inhibit cancer cell migration, an important protein involved in angiogenesis and invasion. HIF-1
anti-angiogenic properties, and via reducing oxidative stress. is a promising target in cancer therapy. The compounds with
The most potent compound 120 exhibited IC50s as 4.28 trifluoromethyl group showed no inhibitive activities on HIF.
(A549), 6.50 (HepG2), 33.21 (HeLa), 21.80 (HTC-116), 23.45 Among all, the compound 137 having 3-hydroxy-4-methoxy sub-
(MCF-7), 25.80(MDA MB 231) [54]. stituent showed potential HIF inhibition rate of 83.0 ± 16.9% by
Base promoted condensation of 4-hydroxyacetophenone down-regulating the expression of HIF-1α under hypoxic condi-
62 and appropriate aldehyde 121 (4-flurobenzaldehyde, tions [57].
4-chlorobenzaldehyde, 4-bromobenzaldehyde) afforded the Markovic and co-workers have synthesized a new class of
unsaturated ketones 122 which were reacted with various hybrid chalcone analogs where in the A-ring has been
amines and paraformaldehyde to afford the corresponding replaced by an anthraquinone moiety starting from 1-acety-
bis-Mannich bases (Scheme 23). The synthesized compounds lanthraquinone 138 in a Claisen Schmidt reaction and evalu-
were evaluated for their cytotoxic and carbonic anhydrase ated for their anticancer potential against three human cancer
enzyme inhibitory effects. CC50 values of synthesized com- cell lines (Scheme 26). Compounds 142, 143 and 144 were
pounds were in the low micromolar range (51.6–18.4 µM) non-cytotoxic and inhibited HeLa cells with IC50s ranging from
toward HSC-2, HSC-3, and HSC-4 cell lines, suggestive of 2.36 to 2.73 µM. Mechanistically, the compounds accumulated
their antineoplastic properties. Cytotoxicities of the com- in S and G2/M phases in a dose-dependent manner and
pounds were compared with reference compounds, induced caspase-dependent apoptosis [58].
Melphalan (alkylating agent) and 5-Fluorouracil (5-FU). Shen and co-workers synthesized various 3,4-dimethoxyl-
According to PSE values, the compounds 124 and 125 proved benzenesulfonates 148 and evaluated their anti-proliferative
Scheme 23. General synthesis of the chalcones and bis Mannich bases. Reagents and conditions: (a) 10% NaOH, EtOH, RT, 24 h. (b) CH3CN, paraformaldehyde,
amine, 45min, 120°C, 200Watt, 13 barr [55].
Scheme 24. Synthesis of novel triazolyl epipodophyllotoxin congeners 128 [56].
Scheme 25. Synthesis of chalcones analogues 136. Reagent and conditions: (a) HCl/CaCl2, Cu/CuCl −15°C, then 0°C 2h (b) K2CO3/KI, PEG-600, reflux, 48 h (c) N,
N-dimethylaniline, reflux, 2h (d) toluene, reflux, 4 h [57].
262 A. RANI ET AL.
Scheme 26. Synthesis of anthraquinone-chalcone derivatives. Reagents and conditions: (a) Benzaldehydes, NaOH, methanol, 5–12 h, reflux (b) Terephthalaldehyde,
NaOH, MeOH, 5h, reflux (c) Acetophenones, NaOH, methanol, 12–36 h, reflux [58].
Scheme 27. Reagents and conditions: (a) aqueous NaOH solution (40%) in methanol, 12 h, RT, 70–90% (b) Et3N in CH2Cl2, 2 hours, RT, 60%-75% [59].
activity against MCF-7, HepG2, HCT116, and Hela cells polymerization inhibitory activity and the results were com-
(Scheme 27). Most of the synthesized scaffolds manifested parable with CA-4, used as the positive control. Molecular
lower IC50s compared to that of colchicine. Among them docking studies of 149 further predicted its interaction with
compound 149 was most potent among the series with IC50s microtubules via π-π and hydrogen bond formation [59].
of 79.2 (MCF-7 and HepG2); 81.34 (HCT-116) and 86.8 nM Tugrak and co-workers have synthesized a series of chalcone
(Hela) along with low cytotoxicity towards normal cell lines. analogs and its mono Mannich bases and evaluated for their
Compound 149 was also evaluated for its tubulin cytotoxicities, selectivity index (SI) and potency selectivity
Scheme 28. Synthesis of mono Mannich bases of 2-(4-hydroxybenzylidene)-2,3-dihydroinden-1-one 152. Reagents and conditions: (a) EtOH, 10% NaOH (b) CH3CN,
amines, 13.8 barr, 200 Watt, 120°C [60].
(Scheme 28). The cytotoxicities of these synthesized compounds

were tested against human tumor cell lines gingival carcinoma
(Ca9-22), oral squamous cell carcinoma (HSC-2, HSC-3, HSC-4) and
human normal oral cells gingival fibroblasts (HGF), periodontal
ligament fibroblasts (HPLF) and pulp cells (HPC) using melphalan
and 5-fluorouracil as standard drugs. Increased cytotoxicities
towards cancer cell lines were observed among Mannich bases
compared to their precursors. The compound 153 having
N-methylpiperazine moiety was most potent with highest potency
selectivity expression PSE (0.2262) value and was more cytotoxic
than melphalan and 5-FU towards HSC-2 and HSC-4 cell lines.
Amines used have different pKa values which may govern the
cytotoxicity by affecting the deamination ratio. PSE values
(0.00145–0.1035) were lower when acyclic amines were used
instead of cyclic amines (0.0566–0.1035). All the compounds
Scheme 29. Preparation of metal complexes 157 with Schiff base ligands. were tumor specific cytotoxins and not toxic towards non-
Reagent and conditions: (a) TSOH, solvent free (b) M(OAc)2.nH2O, TSOH [71]. malignant cells [60].
2.2. Chalcones as anti-bacterial/anti-fungal agents:

synthesis and bio-evaluation
The multidrug resistance among bacteria and fungi is an
alarming and re-emerging threat which has become a major
public health concern, worldwide [61–63]. The intensive use of
antibacterial and antifungal drugs has dramatically increased
the frequency of microbial resistance and led to an increase in
difficult-to-eradicate infections [64,65]. The increase in the
incidence of morbidity and mortality with bacterial/fungal
infections promoted a strong urgency for the development
of new molecules with improved bioactivity and low resis-
tance indices [66–69]. The present section of the review is an
attempt to update the readers on the development of new
Scheme 30. Synthesis of 3-acyl-2-arylpyrrolo[2,3-β]quinoxalines via palladium- chalcones based scaffolds with promising antibacterial and
catalyzed reaction of N-alkyl/benzyl-3-chloroquinoxaline-2-amines with chal-
cones. Reagents and conditions: (a) Pd(OAc)2, KOtBu, NaOAc, DMSO, 100°C [72].
fungal potential [69,70].
Liu et al. described the synthesis and characterization of
Schiff bases viz. 1-ferrocenyl-3- (2-furyl) propenone diamino
expression (PSE). 2-(3-((amino)methyl)-4-hydroxybenzylidene)- (thio) urea 156 and its metal complexes with Pb(Ⅱ), Bi(Ⅲ), Cu
2,3-dihydroinden-1-one types of mono Mannich bases were (Ⅱ), Cr(Ⅲ), Ba(Ⅱ), Cd (Ⅱ), Fe(Ⅱ), Ni(Ⅱ), Sn(Ⅱ), Nd(Ⅱ) (Scheme 29).
synthesized from corresponding [2-(4-hydroxy-benzylidene)- Antimicrobial activities of both the Schiff base ligands and
indan-1-one] using different cyclic and acyclic secondary amines their metal complexes 157 were tested against a panel of
264 A. RANI ET AL.
gram negative strains such as Escherichia coli (ATCC 25922) against P. aeruginosa was better than that of penicillin, used
and Staphylococcus aureus (ATCC 25923) and Methicillin- as the reference antibiotic [72].
resistant S. aureus (MRSA, ATCC 43300), C. albicans and Lal et al. recently reported the synthesis and antimicrobial
A. flavus fungi. The synthesized Schiff base complexes exhib- evaluation of dehydroacetic acid chalcone-1,2,3-triazole-based
ited higher activity than their corresponding ligands while the conjugates 166 as shown in Scheme 31. These conjugates were
introduction of ferrocene resulted in excellent drug superposi- prepared via Cu nanoparticles mediated azide-alkyne cycloaddi-
tion. The Schiff bases 156 and their Cu(II); Cd(II) and Ni(II) tion reactions. The substituent on aryl ring was varied so as to
complexes 157 were also evaluated for anti-proliferative effi- determine the Structure-Activity Relationship (SAR) among the
cacy against mouse leukemia (P-388) and lung cancer (A-549) synthesized conjugates. The synthesized chalcones 166 were
cell lines. The results showed that [Cu(L2)2]·2H2O, [Cd(L2)2]·2H2 tested against four bacterial strains viz. Bacillus subtilis,
O and [Ni(L2)2]·2H2O have better anticancer activity than the Staphylococcus epidermidis, Escherichia coli and Pseudomonas aer-
corresponding Schiff bases. It was observed that [Cu(L2)2]·2H2 uginosa as well as two fungal strains viz. Aspergillus niger and
O (IC50 = 20.02 µM) was more potent against mouse leukemia Candida albicans using ciprofloxacin and fluconazole as the stan-
cells (P-388), but both [Cd(L2)2]·2H2O (IC50 = 17.58 µM) and dard drugs. SAR studies demonstrated that almost the com-
[Ni(L2)2]·2H2O (IC50 = 16.12 µM) have more cytotoxicity against pounds were found potent against all the tested strains. The MIC
lung cancer (A-549) cell lines [71]. of synthesized conjugates against all four fungal strains ranges
Tayebeh et al. have regioselectively synthesized 1-alkyl- between 0.0030 and 0.0372 µM/mL. The most potent of synthe-
2-aryl-3-acyl pyrrolo[2,3-β]quinoxalines 160 via palladium- sized conjugates viz. 167 (Scheme 31), exhibited MIC value of
catalyzed Heck coupling/heteroannulation reaction. Pd(OAc)2 0.0034 µM/mL against E. coli, 168 exhibited MIC value of
promoted reaction of N-alkyl/benzyl-3-chloroquinoxaline- 0.0030 µM/mL against E. coli and B. subtilis while 169 displayed
2-amines 158 with chalcones 159 afforded the desired pro- MIC value of 0.0030 µM/mL against E. coli, B. subtilis and
ducts (Scheme 30). The anti-bacterial efficacy of all the synthe- S. epidermidis. These MIC values were better than the standard
sized compounds against M. luteus and P. aeruginosa was drug Ciprofloxacin (MIC = 0.0047 µM/mL). Similarly, the antifungal
carried out using dilution method. The compound 161 MIC values were found in the range of 0.0064–0.0372 µM/mL.
showed lowest MIC value (MIC = 31.25 µg/mL) These MIC values were found better when compared with the
against M. luteus. The anti-bacterial activity of 161 was standard drug Fluconazole (MIC = 0.0102 µM/mL). SAR studies
reported to be similar to that for tetracycline with strong revealed that, antibacterial study seems to be independent of the
inhibition (MIC, MBC = 31.25 µg/mL) against M. luteus. The nature of electron withdrawing and electron donating groups
anti-bacterial activity of all the synthesized compounds present on the substituents. In case of the antifungal activities, it
Scheme 31. Synthesis of dehydroacetic acid chalcone-1,2,3-triazole conjugates 166. Reagent and conditions: (a) EtOH, piperidine, reflux (b) R1-Br 165, NaN3, H2O, Cu
nanoparticles [73].
Scheme 32. (a) propargyl bromide, K2CO3, DMF, RT (b) NaOH (60%), Ethanol, RT, 4 h. (c) Method A: copper nanoparticles, sodium azide, R2-Br 174, water, 70°C;
4–7 h, Method B: copper nanoparticles, R3-N3 175, water, 70°C, 4-7h [74].
Scheme 33. Synthesis of substituted styryl 2,5-dimethyl-3-thienyl ketones 180 [75].
was observed that the introduction of nitro and fluoro groups chalcone 173 and triazoles (174, 175) were conjugated. The
resulted in the enhancement of activity profiles [73]. Compounds with electron withdrawing substituents on benzene
Cellulose supported copper nanoparticle-promoted synthesis displayed superior activity than with electron releasing groups
of a series of fluorinated chalcone-triazole conjugates 176 was with a preference for nitro and methoxy substituents against
reported by Yadav et al (Scheme 32). The target compounds and majority of the tested microorganisms. Compound 177 with
propargylated chalcones 173 were examined towards various 4-nitro group exhibited better activity than the standard drug
bacterial strains, S. epidermidis (MTCC 6880), B. subtilis (MTCC with MIC value of 0.0032 µmol/mL against E. coli and
441), E. coli (MTCC 16521), P. aeruginosa (MTCC 424) and two S. epidermidis. Compound 177 was also found to be the most
fungal strains viz. A. niger (MTCC 8189) and C. albicans (MTCC potent among the synthesized compounds against P. aeruginosa
227). The antimicrobial screening results revealed that most of with MIC values of 0.0063 µmol/mL [74].
the synthesized conjugates displayed considerable activities Twelve 2,5-dimethyl-3-thienyl chalcones 180 were synthe-
against tested bacterial and fungal strains. The activity results sized via Claisen–Schmidt condensation of 3-acetyl-
showed synergistic effects when two pharmacophoric units, i.e. 2,5-methylthiophene 178 and substituted benzaldehydes
266 A. RANI ET AL.
Scheme 34. Synthesis of novel 2H-Chromene-Chalcone hybrids. Reagents and conditions: (a) NaOH, Ethanol, RT, 18 h [76].
Scheme 35. Synthesis of pyrazine-based chalcones 189. Reagents and conditions: (a) halogenated benzaldehyde, pyridine, Et2NH [77].
179 by Vanangamudi and co-workers (Scheme 33). against of Aspergillus nigeri NCCS 1196 (AN) and Candida
Antibacterial, antifungal, activities of the synthesized chal- albicans NCCS 3471(CA). Of all the screened compounds
cones were evaluated. SAR analysis revealed that the chal- 186 possessing benzothiophenyl showed promising antibac-
cones with -OCH3, -CH3 and -NO2 substituent at C-3 position terial activity which is comparable with standards, Ampicillin
have good antibacterial activity against B. subtilis, M. luteus, and Fluconazole. These results were encouraging as
S. aureus, E. coli, K. pneumonia and P. aeruginosa. Most potent Chalcone-2H Chromene hybrids showed reasonable potential
antibacterial compound 181 having NO2 substituent at C-3 against various bacterial strains and could provide an inroad
showed maximum inhibition zone against E.coli. Compound for designing newer antimicrobial agents [76].
182 with hydroxyl group at 2nd position was active towards all Chlupacova et. al. have designed and synthesised novel
the three fungal strains. It was observed that the chalcone pyrazine based chalcones 189 using Claisen Schmidt conden-
with 4-Cl showed an appreciable antifeedant activity at 200 sation reaction of acetylpyrazine 187 and its 5-alkylated deri-
ppm concentration [75]. vatives with 2/4-halogenated aldehydes 188 (Scheme 35). All
Prabhakar et al. have devised the synthesis and antibac- the synthesized compounds were subjected to the antifungal
terial activity of novel 2H-Chromene-Chalcone hybrids 185 assay wherein the growth inhibition of T. interdigitale by non-
via claisen Schmidt condensation of variedly substituted alkylated compounds was noteworthy. The derivative with
acetophenone derivatives with 2H Chromene aldehydes 2-chloro substitution in the ring B (190) exhibited the best
(Scheme 34). The antibacterial activity of the synthesized activity (MIC 3.9 µmol/L) among synthesized compounds,
compounds 185 was screened against gram-positive comparable to that of fluconazole (MIC 6.51 µmol/L).
Staphylococcus aureus NCCS 2079 (SA) and Bacillus cereus However, the derivative 190 was not as potent as terbinafine
NCCS 2106 (BC) and gram-negative Escherichia coli NCCS (MIC 0.01–1.72 µmol/L), commonly employed for dermatomy-
2065 (EC) and Pseudomonas aeruginosa NCCS 2200 (PA) bac- cosis. 4-Fluoro, 2-bromo or 4-bromo substitution also had
terial strains. Their antifungal activity was also screened inhibiting effect on growth of T. interdigitale (MIC
3.9–7.81 µmol/L). Halogenated derivatives also inhibited the benzoyl hydrazine 199 in the presence of concentrated
growth of Candida spp., which was non-specific by com- hydrochloric acid in refluxing ethanol to afforded target com-
pounds having fluoro-substituent at C-4 position but specific pounds 196, 198 and 200 respectively (Scheme 36). The
(Candida glabrata 20/I and Candida krusei E 28) among chlori- compounds were screened against Gram-positive (S. aureus
nated analogues. All the synthesized hybrids proved to be 4220, S. aureus 209, S. aureus 503 and Streptococcus mutans
active in antibacterial assay specifically against 3065), four clinical isolates of multidrug-resistant Gram-
Staphylococcus spp. Comparing the influence of halogen sub- positive (MRSA 3167 and 3506, and QRSA 3505 and 3519),
stitution, the presence of either 3,5-dibromo or 3,5-bis- four Gram-negative (Escherichia coli 1924, E. coli 1356,
(trifluoromethyl) substituents afforded compounds that Salmonella typhimurium 1926 and Pseudomonas aeruginosa
inhibited the growth of Candida spp. and T. interdigitale [77]. 2742) and fungus (Candida albicans 7535) strains. The synthe-
Piao et. al. has designed three series of chalcone deriva- sized compounds exhibited inhibitory activities against differ-
tives 196, 198, 200 possessing aminoguanidine and acylhy- ent bacterial and fungus strains with MICs ranging from 1 to
drazone moieties via condensation of terephthalaldehyde 64 µg/mL. Among the series, 196 showed antibacterial activ-
193 with substituted acetophenones 192. The synthesized ity with MICs in the range of 1 to 16 µg/mL. Compound 201
chalcones 194 on treatment with aminoguanidine bicarbo- proved to be most potent among the series against fungus
nate 195, isonicotinic acid hydrazide 197 and substituted C. albicans 7535 with MIC of 1 µg/mL, equal to that of
Scheme 36. Synthesis of novel aminoguanidine chalcones. Reagents and conditions: (a) Benzoylhydrazine or isoniazide or aminoguanidine bicarbonate, ethanol,
HCl, 50–60°C, reflux, 8–12 h [78].
Scheme 37. Ferrocenyl chalcone with O-alkylated vanillins 206 [79].

268 A. RANI ET AL.
fluconazole. The presence of substituents on the aryl ring had

a pronounced effect on the activities in the order of 3-Br >
4-Br > 2-Br (among bromo-substituents); 2,4-Cl > 4-Cl > 3-Cl >
2-Cl (among chloro-substituents); and 4-CH3 > 2,4-(CH3)2 > 4-
OCH3 (among electron donating groups). Notably, compound
with 2,4-Cl substituted phenyl ring exhibited moderate activ-
ity against all the tested strains with MICs of 4 to 32 µg/mL,
except for Gram-negative S. typhimurium 1926 and
P. aeruginosa 2742 [78].
Muskinja et al. have reported a series of ferrocenyl chalcones
Scheme 38. Synthesis of 2’ hydroxyl carbazole based chalcones 211. Reagents and with O-alkylated vannilines 206 along with their in vitro antibac-
conditions: (i) KOH, methanol, RT (ii) powdered KOH, Microwave irradiations [80].
terial and antifungal activity using the broth microdilution
method against five species of bacteria and five species of
fungi (Scheme 37). The bacteria used as test organisms in this
study were S. aureus (ATCC 25,923), B. subtilis (ATCC 6633),
B. cereus (ATCC 10,987), E. coli (ATCC 25,922), and P. mirabilis
(ATCC 12,453). The fungi used were S. niger (ATCC 16,888),
C. albicans (ATCC 10,259), P. italicum (ATCC10454), M. mucedo
(ATCC 20,094), T. viride (ATCC 13,233). All the tested compounds
showed similar activity trends. The measured MIC values of
synthesized compounds were in the range of 0.0352 to
0.8873 mg/mL [79].
A new class of chalcone derived from carbazoles 211 was
designed by Dongamanti et al. as potential antimicrobial and
antioxidant agents (Scheme 38). The synthesized compounds
were assayed in vitro for antibacterial activity against two
gram-positive, S. aureus and B. subtilis and two gram-
negative bacterial strains, E. coli and K. pneumonia and anti-
fungal activity against Fusarium oxysporum, Aspergillus niger
and Aspergillus flavus. Most potent compound, 212 showed
2.0 mm inhibition zone against E. coli at 20 µg/mL and 2.6 mm
against A. niger at 100 µg/mL. The promising compounds were
also assayed for their DPPH radical scavenging activity which
indicated that compounds with electron-donating groups
Scheme 39. Synthesis of chalcone based acrylamides homopolymer PAPA 218, (OCH3 and OC2H5) and weak electron-withdrawing groups (Cl
PMNPA 219, PFPA 220 [81]. and Br) improved the antioxidant activity of the com-
pounds [80].
Boopathy et al. have synthesized chalcone-based acrylamide
monomers via Claisen–Schmidt condensation with further poly-
merization using azobisisobutyronitrile as an initiator (Scheme 39).
The antimicrobial activity of naphthalene-, anthracene- and fluor-
ine- incorporated scaffolds viz. PMNPA (219), PAPA (218), and
PFPA (220) was measured using resazurin reduction assay. The
polymers PMNPA and PAPA exhibited enhanced antibacterial and
antifungal activities because of the presence of substituted
naphthyl and anthracenyl moieties. Polyacrylamide (PFPA) based
chalcone showed enhanced antifungal activity without any sign of
antibacterial activity. PFPA (220) displayed a MIC value of 3.12 μg/
mL against C. Albicans. PAPA (218) proved to be active against
Gram-positive S. faecalis with MIC value of 1.56 μg/mL, similar to
that of PMNPA (219) [81].
Prasath et al. synthesized two series of quinolinyl chalcones
223 and 225 having a pyrazole ring via Claisen–Schmidt con-
densation 2-methyl-3-acetylquinoline 222 with either substi-
tuted 1,3-diphenyl-1H-pyrazole-4-carbaldehyde 224 or
5-chloro-3-methyl-1-phenyl-1H-pyrazole-4-carbaldehyde 221.
The synthesized compounds were screened for antibacterial
Scheme 40. Synthesis of quinolinyl chalcones [82]. and anti-fungal activity against various gram-positive and
Scheme 41. Synthesis of some novel substituted pyrazoles. Reagents and conditions: (a) NaOH, 60% EtOH (b) Ac2O [83].
gram-negative bacteria, and fungal strains using agar cup- were evaluated for antimicrobial activities using rifampicin
plate method. Among the compounds studies, the com- and ampicillin as standards. Apart from acetoxysulfonamide
pounds 226 and 227 proved to be most potent with pyrazoles, all other compounds displayed good activity
20.2 mm against C. albicans and 21.4 mm activity against against S. aureus and C. albicans in the order:
E. coli, respectively (Scheme 40). The data revealed that the 239 > 240 > 237 ≥ 238. Minimum bactericidal concentra-
presence of electron-withdrawing groups improved the anti- tion (MBC) was also determined and the chloro-derivatives,
microbial activities while introduction of electron-releasing in particular, 237, 238, 239 and 240 exhibited high activ-
substituents resulted in moderate anti-oxidant activity [82]. ities. The antimicrobial screening using the agar well-
Hamada et al. reported the synthesis of acetoxysulfona- diffusion method revealed that the trend of activity as:
mide pyrazole 235, substituted 4,5-dihydropyrazole-1-car- X > H > OMe > NO2 where X = -Cl, -Br suggestive of the
bothioamide 232 and 4,5-dihydropyrazole-1-isonicotinoyl presence of halogen substituent for good antimicrobial
236 derivatives (Scheme 41). The synthesized scaffolds activity [83].
270 A. RANI ET AL.
Scheme 42. Synthesis of novel chalcone-rivastigmine hybrids. Reagents and conditions: (a) 37% HCl, ethyl alcohol, 70°C, 24–36 h; (b) 8% KOH, CH3OH, 70°C, 24–36 h [106].
Scheme 43. Reagents and conditions: (a) 37% HCl, ethyl alcohol, 70°C, 24–36 h [106].
2.3. Chalcones as anti-alzheimer agents: synthesis and acetylcholinesterase and butyrylcholinesterase by Wang et. al.
bio-evaluation The concept was realized using substituted acetophenones 241
with p-hydoxy 68 or p-methoxybenzaldehyde 243 to afford target
Alzheimer’s disease (AD) is an irreversible, chronic neurode-
compounds in Claisen Schmidt condensation. Another set of
generative disorder responsible for dementia and is consid-
target hybrids 248 were synthesized via aldol condensation
ered as the fifth leading cause of death among elderly people
of m/p hydroxyl acetopheneones 246 with substituted benzalde-
[84–86]. The disease is responsible for affecting 5.7 million
hydes 247.
people in the US in 2015 and is projected to grow to
The designed hybrids were subjected to Ellman assay to mea-
13.8 million by mid-century [87]. AD is thought to affect
sure their inhibitory effect on Acetylcholinesterase hAChE and
about 46.8 million people worldwide in 2015 [88]. However,
butyrylcholinesterase hBChE activity. Rivastigmine was used as
because of complex pathologies associated with AD, the
a positive control and exhibited IC50 value of 0.38 µM.
therapeutic options, including cholinesterase (ChE) inhibitors
Compound 245 was the most potent inhibitor of hBChE with an
and N-methyl-D-aspartate (NMDA) receptor antagonist are
IC50 of 0.36 µM, comparable to that of rivastigmine. Analyzing the
focused on the symptomatic aspects and could not effec-
SAR of the synthesized compounds for their hBChE inhibition
tively inhibit progressive neurodegeneration [89–92].
revealed the following:
A number of pathophysiology factors such as deficits of
acetylcholine (ACh) [93], oxidative stress [94,95], inflamma-
(i) The presence of carbamate at C-3 in the ring improved
tion [95], β-amyloid (Aβ) deposits [96], tau-protein aggrega-
the inhibitory activity while its presence at C-4/C-5
tion [97], and dyshomeostasis [98–101] are considered as
position resulted in the loss of activity.
important key players for the disease progression. Recent
(ii) The presence of disubstituted carbamate in ring
studies have indicated the utility chalcones as Aβ-imaging
A proved detrimental for the activity profiles.
tracers with high brain uptake and affinity for Aβ aggregates
(iii) The presence of alkyl substituents influenced the activ-
suggestive of their potential as a future multifunctional can-
ity profiles in order dimethyl> bis(ethyl(methyl)) >
didate against multi-resistant AD [102–105].
diethyl and the most potent inhibitors were methyl
A trail of novel chalcone-rivastigmine hybrids were prepared
derivatives
and in vitro evaluated for their ability to inhibit human
Scheme 44. (a) Synthetic scheme for the formation of chalcones. (b) Representation of metal (M2+) chelation by the 2-pyridyl ketone moiety, intramolecular hydrogen
bonding preventing metal chelation to the 2-acyl phenol and 2-acyl aniline moieties. Reagent and conditions: (a) aq. KOH, EtOH, RT. (b) NaOH, EtOH, RT [107].
In case of hAChE, the presence of dimethylcarbamate in A ring concentrations, while Aβ1-40 oligomerizes very weakly.
of chalcone resulted in inhibitory activity. The bis(ethyl- Several chalcones were found to exhibit potent disaggrega-
(methyl)) carbamate and diethyl carbamate derivatives proved tion of preformed N-biotinyl Aβ1-42 (bioAβ42) aggregates
to be inactive while disubstituted (C-3 and C-5) carbamate in vitro in the absence and presence of metal ions viz. Cu2+
derivatives also lost the activity similar to hBChE. The most and Zn2+, while others were effective at inhibiting the action
potent hAChE inhibitor, 245 exhibited an IC50 of 0.872 µM, of AChE. Compounds 254 and 255 resulted in an effective
which is approximately three-folds better than that of rivas- modulation of assembly and disassembly of bioAβ42 oligo-
tigmine (Scheme 42 and 43). The synthesized compound 245, mers, both in the presence and absence of metal ions.
with a dual inhibitory activity on both hAChE and hBChE Overall, chalcones with 2-acyl aniline proved to be better
might show a better therapeutic profile in AD and related in vitro AChE inhibitors than the corresponding chalcones,
dementia. The mechanism of enzymatic interactions was which in turn displayed better activity than pyridines. 254
investigated using kinetic experiments, molecular docking, proved to be a multifunctional compound as it exhibited
molecular dynamics simulations, and binding free energies metal-Aβ modulator capability and inhibited AChE activ-
analyses. Compound 245 restricted the formation of reactive ity [107].
oxygen species (ROS) in SH-SY5Y cells and have the relevant
properties in accordance with In Silico ADMET prediction [106].
Fosso and co-workers synthesized three different classes of 2.4. Chalcones as anti-inflammatory agents: synthesis
chalcones along with their bio-chemical evaluation, SAR and bio-evaluation
assessment, metal binding studies and inhibition of AChE/
Inflammation is one of the major causes of various diseases
BChE activity (Scheme 44). The synthesized chalcones were
like arthritis, cancer, cardiovascular, diabetes, obesity, osteo-
evaluated to observe their role on Aβ oligomer assembly and
porosis, inflammatory bowel disease, asthma, and even central
disaggregation. Aβ1-42 in its N-biotinylated form (bioAβ42) was
nervous system (CNS)-related diseases such as depression and
thus used in this anti-oligomer assays because it readily
Parkinson’s disease [108–113]. Literary reports suggest that
assembles into oligomers at near-physiological nanomolar
almost 90% of anti-inflammatory drugs produce drug-related
272 A. RANI ET AL.
toxicities and iatrogenic reactions thus compromising the ities, lipopolysaccharides suppression (LPS)-induced nitrogen
treatment process. Cyclooxygenase (COX) enzymes have oxide generation and in-vitro anti-excitotoxicity. The com-
attracted a great deal of interest as important targets for pounds were found potent against 2,2-diphenyl-1-picrylhydra-
drug discovery due to their essential role in prostaglandin zyl (DPPH) free radical scavenging, (LPS)-induced nitrogen
biosynthesis [114–116]. Inhibition of COX enzymes is oxide generation and anti-excitotoxicity. Chalcone 256 and
a promising approach to pharmacologic intervention in 257 (Scheme 45) were found effective suppressor of NO gen-
inflammation [117]. Among therapeutic agents in clinical use eration at the concentration value of 10 µM. Among all the
today, nonsteroidal anti-inflammatory drugs (NSAIDs) exert biological activities, it was observed that free radical scaven-
their therapeutic action by inhibiting COX enzymes [118]. ging activity was enhanced with the introduction of trimer
The long-term use of NSAIDs may also lead to severe gastro- substituents. Chalcone 258 was displayed better anti-
intestinal side effects, which limit the use of these drugs [119]. inflammatory activities in comparison to 256 and 257, with an
Chalcones are considered as anti-inflammatory agents, which IC50 value of 1 µM. Further, all three chalcones exhibited
may be related to their ability to inhibit cyclooxygenase and considerable anti-neurotoxicity in cultured cortical neurons.
lipooxygenase enzymes [120–122]. Furthermore, the anti-neurotoxic activity was also supported
Jung and Co-workers have reported base promoted synth- by the theoretical calculations of HOMO-LUMO map studies of
esis of chalcones 256–258 as shown in Scheme 45. The reac- synthesized chalcones [123].
tions were carried out with a variety of bases, and the best Abdellatif et al. have synthesized a 4’-flouro-2’-hydroxy
results in terms of yield were obtained using LiOH, presumably chalcones 261 and their corresponding dihydropyrazoles
because of the chelation effect. The characterized chalcones 262. The synthetic methodology involved condensation of
256–258 were assayed for their free radical scavenging activ- 4’-fluoro-2’-hydroxyacetophenone 259 with appropriately
Scheme 45. Reagents and conditions: (a) 1,3-diacetylbenzene, c-H2SO4, ethanol, reflux 3 h; (b) 1,4-diacetylbenzene, c-H2SO4, ethanol, reflux 3 h; and (c)
1,3,5-triacetylbenzene, c-H2SO4, ethanol, reflux 3 h [123].
Scheme 46. Synthesis of 4′-fluoro-2′-hydroxy-chalcone derivatives. Reagents and conditions: (a) Ethabol, NaOH, RT and 2–6 h; (b) Ethanol, hydrazine hydrate, reflux
and 2–4 h [124].
Scheme 47. Synthesis of compounds. Reagents and conditions: (a) H2SO4/HNO3, 0°C, 45 min, 90% (b) 10% Pd/C, H2, EtOH, 3 h, 96% (c) R1CHO, 20% NaOH, EtOH,
overnight, 40–85% (d) 2-hydroxy-3-methoxybenzaldehyde, methanol, over-night, 30–90% (e) R2CHO, methanol, overnight, 20–81% [125].
substituted aldehydes 260 followed by cyclization with dihydropyrazole exhibited the highest activities. The anti-
hydrazine hydrate (Scheme 46). All the synthesized com- inflammatory studies showed that the mono methoxychal-
pounds were evaluated for their antioxidant, anti- cones displayed good anti-inflammatory activity, while the
inflammatory, cyclooxygenase inhibition selectivity and corresponding dihydropyrazoles displayed good anti-
analgesic activities. The antioxidant activity studies showed inflammatory activity. The docking studies further con-
that the dimethoxychalcone and its corresponding firmed that the monomethoxychalcone 263 and its
274 A. RANI ET AL.
Scheme 48. Structures and synthesis scheme of pyrazoline chalcones derivatives. Reagents and conditions: (a) NaOH, EtOH, RT [126].
Scheme 49. Synthesis of O-alkyl azide ferrocenyl-chalcones 286 [140].
cyclized counterpart were better fit into the COX-2 active and exhibited significant protection against LPS-induced
site, which was in parallel correlation with the observed acute lung injury in a mouse model. The potent effects
in vitro COX inhibition [124]. observed in the present series on LPS-induced inflammation
A series of paralleled Aza resveratrol–chalcone compounds suggests that Aza resveratrol–chalcone compounds could be
were designed, synthesized and screened for anti-inflamma- promising for anti-inflammatory drug development [125].
tory activity against LPS-induced IL-6 release in mouse macro- Bukhari and co-workers reported a series of chalcone deriva-
phages by Wenbo and co-workers (Scheme 47). Most of the tives 274 via eco-friendly, and efficient Claisen–Schmidt condensa-
synthesized compounds showed potent inhibition on IL-6 and tion used these as precursors for affording pyrazoline derivatives
TNF-α expression-stimulated by LPS in macrophages along 275, 277 (Scheme 48). The synthesized compounds were assayed
with low toxicity in vitro. The most promising compound for anti-inflammatory related activities such as inhibition of phos-
271 was selected for in vivo anti-inflammatory evaluation pholipase A2 (PLA2), cyclooxygenases (COX-1 and COX-2), release
Scheme 50. Synthesis of piperazine-linked 7-chloroquinoline-ferrocenylchalcone conjugates 290.
Scheme 51. Synthesis of phenyl linked 7-chloroquinoline-ferrocenylchalcone conjugates 295.
Scheme 52. Synthesis of amino alcohol linked 7-chloroquinoline-ferrocenylchalcone conjugates 298 [140].
of pro-inflammatory cytokines including IL-6 and TNF-a. Analysis of 2.5. Chalcones as anti-malarial agents: synthesis and
the results revealed that among chalcone derivatives, 278 exhib- bio-evaluation
ited good inhibition with IC50 value 12.72 µM, 280, on the other
Malaria is a parasitic infectious disease that continues to have
hand, was most potent among the 2-pyrazoline-1-carbothioa-
a significant impact on global health outcomes [127].
mides, while compounds 281 and 283 were the most potent
According to the WHO report 2017, there are an estimated
inhibitors of sPLA2 among 2-pyrazoline-1-carboxamides. SAR ana-
216 million cases and 445,000 deaths resulting from malaria
lysis revealed that the presence of o,p-dimethoxy substitution on
globally [128]. Despite widespread implementation of anti-
naphthalene ring improved the activity while the anti-inflamma-
malarial drugs and insecticide controls in malaria-endemic
tory activity of pyrazoline derivatives was augmented with the
regions, current treatment options and preventative measures
presence of carbothioamide moieties. The results of this study
are limited in their effectiveness [129,130]. In particular, drug-
showed that the synthesized compounds were effective inhibitors
resistant strains of the Plasmodium parasite present a major
of pro-inflammatory enzymes and cytokines, which was further
challenge for disease prevention. The influence of specific
supported by Molecular docking studies [126].
genes on parasitic virulence is widely recognized, making it
276 A. RANI ET AL.
Scheme 53. Synthesis of piperazine-tethered 4-aminoquinoline-chalcone 302 and 4-aminoquinoline-ferrocenylchalcone 303 conjugates [141].
Scheme 54. Synthesis of (2-Azido-ethyl/propyl)-(7-chloro-quinolin-4-yl)-amine 305. Reagents and conditions: (a) Ethanol/propanolamine, Et3N, 120°C, 12 h (b) MsCl,
Et3N, dry CHCl3, 0°C-RT, 2–3 h (c) NaN3, DMF, 120°C, 12 h [142].
difficult for researchers to develop an effective malaria vaccine chalcones via Cu-promoted azide-alkyne cycloadditions and
[131,132]. Chalcones have well-established role as cysteine evaluated their anti-plasmodial activity (Scheme 49-52). The
protease inhibitors as well as inhibitors of aspartic protease presence of a flexible chain on the quinoline core improved
which mediates protein hydrolysis via nucleophilic attack on anti-plasmodial efficacy while the presence of cyclic piper-
a carbonyl of a susceptible peptide bond. It is also reported azine/aminophenol functionalities was detrimental to the
that the chalcones inhibit parasite-induced permeation path- activities. The scaffolds with amino alcohols (amino-
ways in host RBC’s membrane [133–139]. In this review, the propanol) as substituents proved to be non-cytotoxic with
essential structural requirement in the rational design and activities in the sub-micromolar range (0.37–1.78 µM). The
development of antimalarial lead candidates based on chal- most potent and non-cytotoxic conjugate 299, exhibited an
cones are focussed with an emphasis on their SAR and ther- IC50 value of 0.37 µM against the chloroquine-resistant W2
apeutic targets. strain of Plasmodium falciparum [140].
Singh and co-workers have synthesized a series of Singh and co-workers synthesized a series of piperazine-
1H-1,2,3-triazole linked 7-chloroquinoline-ferrocenyl tethered 4-aminoquinoline-chalcone/ferrocenyl-chalcone
Scheme 55. Synthesis of acetylenic chalcones 309 and their corresponding pyrazolines 310. Reagents and conditions: (a) K2CO3, DMF, RT, 2 h (b) KOH, EtOH, 30min-
2 h (c) Hydrazine hydrate, Acetic acid, reflux, 2–3 h [142].
Scheme 56. Synthesis of 4-aminoquinoline-chalcone conjugates 311 and 4-aminoquinoline-pyrazoline 312 conjugates. Reagents and conditions: (a) CuSO4.5H2O,
Sodium ascorbate, EtOH:H2O, RT, 7–8 h [142].
conjugates and evaluated their anti-plasmodial activities P. falciparum. SAR studies confirmed the activity-dependence
(Scheme 53). In vitro IC50s ranging from 0.41 to 2.38 µM were on the length of the alkyl chain, while the electronic nature of
observed against chloroquine-resistant W2 strain of substituent at ring B of the chalcone did not seem to affect
278 A. RANI ET AL.
activity. The compound 304, with an optimum combination of amide having a piperazine ring as linker displayed moderate
hexyl chain length as a linker and un-substituted phenyl (ring B) anti-proliferative activities as shown in Scheme 57 [143].
ring, proved to be most potent among the series and exhibited
an IC50 value of 0.41 µM, associated with the index of selectivity
2.6. Chalcones as anti-oxidant agents: synthesis and
of around 46.7. The sub-micromolar activities of most of the
bio-evaluation
synthesized conjugates suggest that such molecular frameworks
can act as therapeutic templates for the design and synthesis of Oxidative stress, caused by an imbalance between pro-oxidant
new antimalarials [141]. and antioxidant homeostasis leads to the generation of toxic
Raj et al. have synthesized and evaluated a library 4-ami- radical species [144]. Antioxidants are chemical species cap-
noquinoline-chalcone/-N-acetyl-pyrazoline conjugates against able of capturing free radicals responsible for many diseases
cultured chloroquine (CQ) resistant P. falciparum strain such as cancer, hyperuricemia, cell aging, and cardiovascular
(Scheme 54-56). The results of anti-plasmodial activities problems [145]. They act via direct scavenging of reactive
revealed the dependence on alkyl chain length along with oxygen species (ROS), i.e. inhibition of enzymes responsible
the presence of – OCH3 substituents on ring A/ring B of the for the production of ROS and chelation of metals such as iron
chalcone. 4-aminoquinoline-pyrazoline conjugate 313 was the and copper [146]. In addition to natural antioxidants such as
most potent and non-cytotoxic among the series with an IC50 phenolic compounds, many experimental and theoretical
value of 53.7 nM [142]. efforts have resulted in the identification of chalcones as
A series of novel aminoferrocenyl-chalcone amides 318 was potent antioxidants because of their ability to scavenge reac-
synthesized by Smit and co-workers and evaluated their anti- tive oxygen species and free radicals [147–150].
plasmodial profiles against chloroquine-sensitive 3D7 and chlor- Tajammal and co-workers reported the synthesis (Scheme 58)
oquine resistant FCR3 strains of P. falciparum. The synthesized and antihyperglycemic and antioxidant activity of chalcones and
amides 318 were found to be active in general with IC50 values flavanones. Antioxident activity was compared with control
ranging between 0.5–4.5 and 2.1–6.6 µM against 3D7 and FCR3 Trolox and Ascorbic acid. All the chalcones were found to be
strains, respectively. The compound featuring a 2-aminoethylene more potent than the controls used (Trolox IC50 = 252.73 and
319 linker proved to be the most potent among the series Ascorbic acid IC50 = 240.47 µM) with IC50 values of 50.88, 111.58
displaying IC50 values of 2.6 (3D7) and 2.1 µM (FCR3). The and 167.71 µM for compounds 323a-c respectively. Chalcone
synthesized compounds were also screened against a panel of 323a also exhibited good antioxidant activity while the corre-
cancer cell lines viz TK-10, UACC-62, and MCF-7. Although the sponding flavones, 324a-b were found inactive against DPPH
compounds were not as cytotoxic as the standard drug, the radical scavenging. In Iron chelating activity, the synthesized
Scheme 57. Synthesis of aminoalkylferrocenyl chalcone amides 318. Reagents and condition: (a) Appropriate diamine, MeOH, 4 h, RT then NaBH4 MeOH, 2 h, RT;
piperazine, NaBH(OAc)3, THF, 24 h, RT, CDI, CH2Cl2, 3 h, RT, 24 h, RT (b) 2-acetyl-5-methylfuran, MeOH, NaOH, 12 h, RT (c) Chalcones, CDI, CH2Cl2, 3 h, RT then
ferrocenylamine, 24 h, RT [143].
Scheme 58. Synthesis of substituted hydroxychalcones and hydroxyflavanones [151].
compounds reduced Fe3+ to Fe2+ which involved in the forma- phenyl ring resulted in the enhancement in agonist activity,
tion of chelate with o-phenanthroline. This method is used to while the introduction of electron donating group resulted in
determine the extent of reduction of ferric ions by synthesized the increase in antioxidant activity behavior [148].
compounds. IC50 value for iron chelating activity of each com- Ahmad et al. has devised novel furan based chalcone deri-
pound was determined. Compound 323a again predominated in vatives 339 using microwave assisted claisen-schmidt conden-
the chelation phenomenon with the lowest IC50 value of sation reaction of 1-(5-methylfuran-2yl) ethanone 337 with
0.31 µM, comparable to the control Trolox (IC50 = 0.28 µM) and substituted benzaldehydes 338. (Scheme 60). All the chal-
Ascorbic acid (IC50 = 0.31 µM). No significant difference was cones 339 were tested for cytotoxic activity by Brine shrimp
found between 323a and reference compounds. Chalcone lethality test (BSLT) bioassay method. Among the synthesized
323b also exhibited significant chelating behavior with iron compounds 339, showed dose-dependent cytotoxicity at con-
with an IC50 value of 0.41 µM. In FeCl3 reducing power assay centrations of 24.27 µg/ml for R = H, 37.05 µg/ml for 4-Cl and
the chalcones and flavanones reduced potassium ferricyanide 39.26 µg/ml for 4-F, respectively, with Podophyllotoxin as the
(Fe3+) to potassium ferrocyanide (Fe2+) which then reacted with standard drug. The in vitro antioxidant activity and scavenging
ferric chloride to formferric ferrous complex. FeCl3 reducing effects of 339 were also evaluated by using different reactive
power activity also followed the similar trend with compound species assay containing radical scavenging activity. The
323a exhibiting IC50 value of 9.11 µM better than both the potency of the chalcone derivatives was estimated by IC50
controls used i.e. Trolox (IC50 = 10.06 µM) and Ascorbic acid values. DPPH (1,1-diphenyl-2-picrylhydrazyl) radical scaven-
(IC50 = 12.74 µM). Compound 323a also exhibited excellent ging activity was measured for the synthesized chalcones
antihyperglycemic activity in diabetic rats while the compound 339. The compounds showed a dose-dependent inhibition of
(323c) suppressed the hyperglycemia more effectively in normal radicals at concentrations of 25, 50 and 100 µg/mL, with
rats [151]. ascorbic acid as the standard for comparing results.
Niu and co-workers reported the synthesis of a new class of Compound 340 (4-NO2) appeared to be the best among all
anti-oxidant and PPARα/γ agonist coumarin-chalcone fibrates the tested compounds with IC50 49.18 µg/ml. SAR analysis
(Scheme 59). R substituents were varied so as to compare the showed the presence of substituents like fluorine, chlorine as
structure-activity relationships of the synthesized scaffolds. dichloro and nitro pharmacophore especially at C-4 position of
The PPARα/γ agonist activity results were compared with the aromatic ring-B, improved the cytotoxic and antioxidant activ-
standards, Fenofibrate, and Rosiglitazone. The PPARα agonist ities [152].
results revealed that the compounds 333, 334 and 335 were
found to be most active with the EC50 values of 12.69, 6.99
2.7. Chalcones as anti-tubercular agents: synthesis and
and 11.03 µM. Compound 334 was found four-fold more
bio-evaluation
potent when compared with standard Fenofibrate (EC50
= 30 µM). The compounds 333 (EC50 = 5.19 µM), 334 (EC50 Tuberculosis (TB), an infection caused by Mycobacterium tuber-
= 0.91 µM), and 335 (EC50 = 11.03 µM), exhibited potent culosis (Mtb), remains a serious health problem worldwide
agonist activities against PPARγ, which confirmed the dual [153]. According to the World Health Organization (WHO)
agonist behavior of these compounds. The radical scavenging statistics, approximately 10.0 million new cases of TB were
potential of these compounds confirmed them to be good reported in 2017 with mortality of 1.3 million [154]. The inno-
antioxidant agents. Antioxident results were compared with vative focus on TB has partly been triggered by the persistent
standard Trolox having IC50 vaule of 28.84 µM, while the larger number of TB cases studied in developing countries,
synthesized compounds exhibited IC50 values in the range of and partly by the increased occurrence of multidrug and
8.51 to >100 µM. The compounds 335 and 336 showed the extensively drug-resistant TB (MDR- and XDR-TB) [155–160].
best IC50 values 8.51 and 9.40 µM among the series which A number of natural and synthetic chalcones have been iden-
clearly indicated the better antioxidant behavior of these tified exhibiting anti-mycobacterial activity [161–168].
compounds. The structure-activity comparisons revealed that Licochalcone A, present in Glycyrrhiza inflata exhibited potent
the introduction of electron withdrawing substituent on the anti-tubercular activity (MIC = 7.1 µg/mL) [169–171]. In vitro
280 A. RANI ET AL.
Scheme 59. Reagents and conditions: (a) K2CO3, CH3CN, reflux, 4 h (b) (EtO)2CO, NaH, THF, O °C to RT for 4–5 h (c) substituted salicylaldehydes, piperidine, acetic
acid, absolute EtOH, reflux, 2–5 h. (d) NaBH4, pyridine, RT, 2h, then aq HCl. (e) 10% NaOH-EtOH, 50°C, 1 h [148].
Scheme 60. Synthesis of chalcone derivatives 339 by microwave irradiations [152].
and in silico studies confirmed lipophilicity as one of the a promising potential as future anti-tuberculars and the recent
important factors influencing the anti-tubercular activity of upsurge in this field is presented here.
chalcones that allows them to easily penetrate the mycobac- Desai et al. have reported the synthesis of series of variedly
terial cell wall [172,173]. Chalcones, therefore possess substituted quinoxalinyl chalcones 343 using Claisen Schmidt
Scheme 61. Synthetic route towards quinoxalinyl chalcones from glucose. Reagents and conditions: (a) H2O, o-phenylene diamine, glacial CH3COOH, NH2-NH2·H2O,
reflux, 5 h, cool in ice bath (b) H2O, NaIO4, glacial CH3COOH, RT 16 h (c) Aromatic ketones, NaOH, H2O, EtOH, RT (d) Ice, conc. HCl [174].
Scheme 62. Reagents and conditions: (a) H2SO4 conc. AcOH, reflux, 100°C, 4–24 h (b) 20% NaOH, EtOH, RT, 10 h [8].
condensation, along with molecular docking studies and anti-TB conditions using MABA and LORA assays, respectively.
evaluation against H37RV strain by Alamar blue dye method Compounds containing substituents in the para-position of ring
(Scheme 61). The results were compared with molecular docking A, and heteroaromatics ring B were the most potent among the
studies carried out on M. tuberculosis enzyme enoyl ACP reduc- series. The most potent compound 349 exhibited MIC = 0.19 µM
tase using Surflex-Dock program. The most potent compounds (MABA) and MIC = 1.73 µM (LORA). The substitution of furan ring
of the series 344, 345 exhibited MIC of 3.12 µg/mL comparable by thiophene or nitro-substituted thiophene led to 5.5-folds
to standard drugs, Pyrazinamide and Ciprofloxacin. Replacement increase of the activity in MABA (1.05 µM-0.19 µM) and four-
of aryl ring with pyridinyl enhanced the anti-tubercular activity. folds for LORA (6.94 µM-1.73 µM). Nitrothiophene analogs, unlike
The replacement of aryl with naphthyl ring decreased the activity their nitrofuran analogs, were inactive (MIC>10 µM) in both
of the compound suggestive of the fact that lipophilicity has an MABA and LORA assays. All tested compounds were potent
adverse effect on the anti-TB activity. Molecular docking studies against resistant strains with MIC <1 µM. Compound 350 was
further confirmed the interactions of 344 and 345 with enoyl the most potent compound with MIC of 0.07 and <0.03 µM
ACP reductase enzyme, proving them to be most active of the against rRMP and against rINH strains, indicating that this com-
synthesized series [174]. pound is promising for RMP and INH resistant strains. The series
Gomes et al. synthesized nitrofuran, nitrothiophene, and exhibited good with very low cytotoxicity against Vero cells
chlorothiophene containing chalcone-based anti-TB compounds (SI = 11–545) [8].
via in silico design and QSAR-driven approach (Scheme 62). The Veliz et al. synthesized quinoxaline-chalcone derivatives via
synthesized compounds were assayed against M. tb. H37Rv, a sequence of synthetic steps elucidated in Scheme 63 and eval-
under both aerobic (replicating) and anaerobic (non-replicating) uated their antimycobacterial activity. The MIC of the quinoxaline
282 A. RANI ET AL.
1,4-di-N-oxide derivatives were determined against M. Tb. H37Rv Joshi et al. reported the synthesis and anti-tubercular
(ATCC 27,294) using BacTiter-Glo (BTG) microbial cell viability evaluation of pyrrolyl derivatives 361, 363 (Scheme 64).
assay. The compound 356 was the most active with MIC and IC50 Molecular docking was carried out on enoyl ACP reductase
values of among 1.05 µg/mL and 0.05 µg/mL, lower than that of (InhA) using Surflex-Dock, which is one of the key enzymes
the second-line drugs, cycloserine and pyrimethamine, and the involved in type II fatty acid biosynthetic pathway. Docking
first-line drug, ethambutol. The presence of an electron withdraw- results indicated the occupation of substituted pyrrolyl deri-
ing substituent (-Cl) in the quinoxaline ring was important for vatives into the hydrophobic pocket of InhA enzyme.
biological activity. Compound 356 was active against isoniazid, Compounds 364–367 exhibited moderate anti-tubercular
rifampicin and ofloxacin-resistant strains suggesting that it could activity with a MIC value of 12.5 µg/mL. All other compounds
act through a different mechanism of action than that of reference displayed MIC values in the range of 12.5–50 µg/mL with no
drugs [175]. apparent cytotoxicites towards human lung cancer cell-line
(A549) [176].
Scheme 63. General synthesis of quinoxaline 1,4-di-N-oxide derivatives. Reagents and conditions: (a) DMF, NaOCl, low temperature; (b) ethanolamine, CaCl2 (c)
microwave (d) NaOH, MeOH, ice bath [175].
Scheme 64. Synthetic route of a novel series of pyrrole chalcone derivatives. Reagents and conditions: (a) EtOH, 40% NaOH [176].
3. Conclusion
The chemistry of chalcones has continued to attract the interest
of synthetic chemists because of its accessibility and vulnerabil-
ity while the medicinal chemists will always be inspired by the
diverse biological activities, this moiety is blessed with. The
present review is an attempt to take the readers on an odyssey
of this fascinating molecular fragment with an enormous poten-
tial in drug-design and discovery. Among anticancer chalcones,
the various structural features aiming at different therapeutic
targets viz. tubulin polymerization, caspase-dependent apopto-
sis, obstruction of G2-phase, PI3k/AKT/mTOR signaling pathway,
inhibiting actin polymerization has been discussed. Besides its
anti-proliferative potency, disclosure of their anti-plasmodial, Figure 2. Different biological activities displayed by chalcone analogues.
anti-tubercular, anti-alzheimer activities is worth mentioning
where the structural modifications of chalcones have resulted
in the identification of potential candidates among the known metastasis. Apart from the well-established role as anti-oxidants
inhibitors. The SAR studies, in general, have revealed that the and anti-proliferatives, chalcones are also known for their excel-
induction of electron-donating/withdrawing substituents on lent anti-inflammatory and anti-microbial profiles (Figure 2).
both ring A and B influenced the observed activity profiles The ease of synthetic accessibility from inexpensive and
while the impact was higher when the aryl/heteroaryl ring was easily available precursors along with their safety profiles has
replaced with ferrocene. Chalcones, therefore have enormous made chalcones an engrossed chemical template. Although,
future prospects contemplated as potential candidates against huge amount of literature is published on the biological profiles
various diseases, with well-defined mechanism of action. of chalcones, the chalcone-chemistry still seems to be one of the
However, the careful analysis of reported SAR as a strong pro- most important areas for generating new opportunities in drug
totype for affording effective chalcone-based inhibitors must be design and discovery. The promising compounds of the present
emphasized for future endeavors. review with significant biological activities can serve as impor-
tant therapeutic templates targeting various infectious diseases.
Depending on the requisite structural modulation for improving
4. Expert opinion a particular biological activity and at the same time, minimizing
cytotoxicity and incidence of resistance, we believe that new
1,3-diphenyl-2-propene-1-one, commonly referred as ‘the chal-
effective scaffolds can be developed from chalcones with an
cone’ is an important core in many natural products and was
added advantage of being available at low cost.
first synthesized in 1800. These are abundant in edible plants
and are considered as important precursors for affording flava-
noids and isoflavanoids. Natural chalcones have been found in Funding
hearthwood, bark, leaf, fruit, and root of a variety of trees and
The authors are funded by the Council of Scientific and Industrial Research
are involved in UV filtration, symbiotic nitrogen fixation and via a Junior Research Fellowship (Reference No. 09/254(0269)/2017-EMR-1)
floral pigmentation. Of the various methods developed for provided to A Rani.
affording chalcones, Claisen-Schmidt condensation is consid-
ered as the most classical and efficient method. The presence
of double bond in conjugation with carbonyl functionality is Declaration of interest
considered responsible for the medicinal and biological activ- The authors have no relevant affiliations or financial involvement with any
ities of chalcones. The chalcones have been reported to possess organization or entity with a financial interest in or financial conflict with
the subject matter or materials discussed in the manuscript. This includes
various biological activities including anti-cancer, antimicrobial,
employment, consultancies, honoraria, stock ownership or options, expert
anti-inflammatory, antioxidant, anti-influenza, inhibition of tyro- testimony, grants or patents received or pending, or royalties.
sinase, antiviral, anti-tubercular, antihyperglycemic, anti-
Alzheimer, and anti-malarial properties. Most of the biological
activities of chalcones are because of their interactions with Reviewer disclosures
enzymes, such as trypsine, kinases, and topoisomerases. Peer reviewers on this manuscript have no relevant financial or other
Interestingly, chalcones exhibit both pro- and antioxidant activ- relationships to disclose.
ity, or in other words they can induce or inhibit oxidative stress.
This dual property is well supported by studies showing them to
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Expert Opinion on Drug Discovery

ISSN: 1746-0441 (Print) 1746-045X (Online) Journal homepage: https://www.tandfonline.com/loi/iedc20

Recent developments in biological aspects of

Anu Rani, Amit Anand, Kewal Kumar & Vipan Kumar

To link to this article: https://doi.org/10.1080/17460441.2019.1573812

Published online: 18 Feb 2019.

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Recent developments in biological aspects of chalcones: the odyssey continues

ABSTRACT ARTICLE HISTORY

1. Introduction scientific reports appeared lately (2015–18) on the synthesis

chalcone-based scaffolds with potential therapeutic applica-

23 against human Raji B-cell lymphoma, human JeKo-1 mantle

Scheme 12. Synthesis of 1H-1,2,3-triazole-linked isatin-ferrocenylchalcone conjugates 66 [44].

Scheme 16. Synthesis of variedly substituted chalcones [48].

Scheme 19. Terpenoid like chalcones [51].

Scheme 20. Synthesis of Ru(II) complexes with substituted chalcones [52].

Scheme 24. Synthesis of novel triazolyl epipodophyllotoxin congeners 128 [56].

(Scheme 28). The cytotoxicities of these synthesized compounds

2.2. Chalcones as anti-bacterial/anti-fungal agents:

Scheme 33. Synthesis of substituted styryl 2,5-dimethyl-3-thienyl ketones 180 [75].

Scheme 37. Ferrocenyl chalcone with O-alkylated vanillins 206 [79].

fluconazole. The presence of substituents on the aryl ring had

Scheme 49. Synthesis of O-alkyl azide ferrocenyl-chalcones 286 [140].

Scheme 50. Synthesis of piperazine-linked 7-chloroquinoline-ferrocenylchalcone conjugates 290.

Scheme 51. Synthesis of phenyl linked 7-chloroquinoline-ferrocenylchalcone conjugates 295.

Scheme 58. Synthesis of substituted hydroxychalcones and hydroxyflavanones [151].

Scheme 60. Synthesis of chalcone derivatives 339 by microwave irradiations [152].

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