Journal of Molecular Structure: THEOCHEM 717 (2005) 139–152

www.elsevier.com/locate/theochem

Conformational analysis of some new derivatives of

4-nitroimidazolyl-1,4-dihydropyridine-based calcium channel blockers
Bahram Hemmateenejada,b,*, Ramin Miria, Mohhamad A. Safarpourb,c,
Mehdi Khoshneviszadeha, Najmeh Edrakia
a
Medicinal & Natural Products Chemistry Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
b
Chemistry Department, Shiraz University, Shiraz, Iran
c
Chemistry Department, School of Basic Sciences, Persian Gulf University, Boushehr, Iran
Received 28 August 2004; accepted 25 October 2004
Available online 22 January 2005

Abstract
Molecular mechanic (MMC), semi empirical (AM1) and ab initio (RHF/6-21G) calculations were employed to obtain the optimum 3D
structure of some recently synthesized 4-nitroimidazolyl-1,4-dihydropyridine derivatives as calcium channel antagonists. MMC calculation
was conducted in the gas and aqueous phase and the others were used only for gas phase calculations. The conformation of dihydropyridine
ring (DHP), position of aryl group with respect to DHP ring, conformation of ester groups and the heat of formation (DHf) of these
compounds were investigated. In addition, we studied how the protonation of the nitrogen of DHP ring influenced 3D structures. It was found
that MMC and AM1 produced relatively similar results, while the results of ab initio method were very different from the other methods. All
the computation methods suggested a flattened boat-like conformation for the DHP ring of the studied molecules. However, a slight deviation
from the planarity was observed for some molecules. The calculated heat of formations indicated that the 3D structures obtained by AM1
method were more stable than those resulted from MMC method. Moreover, it was obtained that addition of a proton to the DHP derivatives
decreased the stability of the molecules.
q 2004 Elsevier B.V. All rights reserved.

Keywords: Dihydropyridine; Conformational analysis; Molecular mechanics; Semi empirical; Ab initio

1. Introduction analogues have been the subject of a great deal of

investigations, both from theoretical and experimental
4-Aryl-1,4-dihidropyridines (DHPs) are the most studied point of views [12–17]. Despite many studies on the
class of organic calcium channel modulators, and since their structure–activity relationsthip of DHP derivatives, there
introduction into clinical medicine in 1975, this class has have been still remained debates on the exact sterochemical/
found widespread uses for the treatment of cardiovascular conformational requirements for activity [18]. The X-ray
disease [1]. Nifedipine, as the prototype of 1,4-DHP crystal structure of some DHPs determined that 1,4-DHP ring
structure, has been found useful in both antianginal and adopted a boat conformation [19,10]. It was proposed that
antihypertensive therapy [2]. In recent years, interest has calcium channel modulation (agonist vs antagonist activity)
also focused on the other analogues, which show a similar was dependent on the absolute configuration at C-4 [20].
pharmacological profile and superior in potency of anti- Besides, the other studies confirmed flexibility of both ester
hypertensive activity to classical DHPs drugs [3–11]. group of DHPs and C-4 aryl of these compounds [10,21].
As important tools for the study of calcium channel Some conformational analyses of 4-phenyl DHP was already
structure and function, the conformational features of DHP carried out and confirmed these findings [10,11,21].
Very recently, Knuas and coworkers synthesized new
generations of the DHP derivatives, in which the phenyl
* Corresponding author. Tel.: C98 711 230 3872; fax: C98 711 233
2225. substituent on the C-4 position of the DHP ring was replaced
E-mail address: hemmatb@sums.ac.ir (B. Hemmateenejad). by the other aromatic substituents such as pyridine [22–26].
0166-1280/$ - see front matter q 2004 Elsevier B.V. All rights reserved.
doi:10.1016/j.theochem.2004.10.071
140 B. Hemmateenejad et al. / Journal of Molecular Structure: THEOCHEM 717 (2005) 139–152

Table 1
Structure and activity data of the DHPs used in this study

Nam R1 R2 n Log1/IC50a Name R1 R2 n Log1/IC50a

Nfn1 Me t-Butyl 0 9.74 Nfn23 Et i-Propyl 0 11.29
Nfn2 Me OH 2 11.89 Nfn24 Et t-Butyl 0 10.31
Nfn3 Me COCH3 3 11.83 Nfn25 Et Methyl 0 11.13
Nfn4 Me OCH3 2 11.38 Nfn26 Et OH 2 11.45
Nfn5 Me c-hexyl 0 9.01 Nfn27 Et OCH3 2 11.12
Nfn6 Me c-hexyl 1 8.57 Nfn28 Et c-hexyl 0 8.39
Nfn7 Me c-hexyl 2 8.40 Nfn29 Et c-hexyl 1 9.26
Nfn8 Me c-hexyl 3 8.33 Nfn30 Et c-hexyl 2 7.82
Nfn9 Me c-hexyl 4 8.30 Nfn31 Et c-hexyl 3 8.28
Nfn10 Me c-pentyl 3 8.73 Nfn32 Et c-hexyl 4 8.22
Nfn11 Me Phenyl 1 7.70 Nfn33 Et c-pentyl 3 8.39
Nfn12 Me Phenyl 2 7.67 Nfn34 Et Phenyl 1 7.68
Nfn13 Me Phenyl 3 7.61 Nfn35 Et Phenyl 2 7.56
Nfn14 Me Phenyl 4 7.57 Nfn36 Et Phenyl 3 7.42
Nfn15 Me Phenyl 5 7.14 Nfn37 Et Phenyl 4 4.21
Nfn16 Me p-tolyl 2 7.89 Nfn38 Et Phenyl 5 7.08
Nfn17 Me ONO2 2 11.59 Nfn39 Et p-tolyl 2 7.32
Nfn18 Me ONO2 3 11.33 Nfn40 Et ONO2 2 10.93
Nfn19 Me ONO2 4 11.60 Nfn41 Et ONO2 3 11.11
Nfn20 Me N(CH3)2 3 8.14 Nfn42 Et ONO2 4 10.87
Nfn21 Me N(CH3)2 2 8.50 Nfn43 Et N(CH3)2 3 8.96
Nfn22 Et n-butyl 0 11.49 Nfn44 Et N(CH3)2 2 9.31
a
IC50 is the concentration of the molecules which produce 50% of the desirable activity.

In our research group, we synthesized some new derivatives

of DHP containing a 1-methyl-5-nitro-imidazol-2-yl sub-
stituent at the C-4 position and different ester substituents on
the C-3 and C-5 positions of the DHP ring [3–6]. The
calcium channel antagonist activity of the compounds in
Guinea-pig Ileal was determined in our laboratory and it
was found that the activity of some derivatives was higher
than that of nifedipine [3–6]. Also, we conducted some
quantitative structure activity relationship analysis on these
compounds [27–30] and found that lipophilicity, steric and
electronic properties were the major factor controlling the
binding of these molecules to their receptor. In our
continuing studies on the structure–activity relationships
of these types of compounds, we mainly focused on confor-
mational structure of 4-(1-methyl-5-nitro-2-imidazolyl)
dihydropyridine compound in gas and liquid phases.
Therefore, the conformation of DHP ring, position of aryl
group with respect to DHP ring, conformation of ester
groups, and heat of formation (DHf) of these compounds,
were investigated by using molecular mechanics, semi Fig. 1. The 3D representation and numbering of the basic unit of the DHP
empirical and ab initio calculations. In addition, derivatives used in this study
 B. Hemmateenejad et al. / Journal of Molecular Structure: THEOCHEM 717 (2005) 139–152 141

Table 2
In gas phase optimized dihedral angles (8) and DHf (Kcal/mol) for the most stable conformers of the studied DHP derivatives, obtained by molecular
mechanic/MMC calculation

Compound 1 0 -4-3-2 2 0 -1 0 -4-3 1-2-3-4 7-8-9-10 2-3-5-6 2-3-7-8 5-6-9-10 H 4–CH3 4-3-7-8 4-5-9-10 DHf
Nfn1 109.3 90.3 -4.3 -164.8 -0.2 -1.2 177.2 166.9 -179.8 -0.3 -20.1
Nfn2 94.7 55.9 K0.9 K152.8 K0.8 0.4 177.9 128.2 K179.9 K0.9 K58.3
Nfn3 109.2 90.1 K4.4 K162.6 K0.3 K1.8 179.1 167.1 179.7 K0.6 K61.3
Nfn4 94.2 55.5 K0.7 K152.6 K0.1 0.3 177.7 128.1 K179.8 K1.1 K54.9
Nfn5 76.4 5.0 0.7 140.9 0.1 179.5 K2.0 40.8 K0.8 177.7 K32.6
Nfn6 85.4 41.9 0.8 147.0 K0.1 179.3 2.1 122.8 K1.4 K178.1 K35.5
Nfn7 77.7 11.5 1.2 145.6 0.3 K179.6 3.5 69.6 K1.0 K178.6 K45.8
Nfn8 79.7 19.6 1.1 145.9 K0.1 K179.9 3.7 85.9 K1.2 K178.0 K49.9
Nfn9 77.9 12.1 1.3 145.9 0.1 K179.5 3.7 72.7 K1.0 K178.4 K58.0
Nfn10 90.8 53.6 K0.1 147.3 K1.0 178.3 1.4 134.7 K1.1 K178.7 K35.6
Nfn11 84.4 K18.8 K1.0 149.9 0.3 K179.0 0.9 21.1 K0.2 K179.7 11.9
Nfn12 77.5 11.9 1.3 145.7 0.3 K179.9 4.1 68.0 K1.2 K178.2 10.5
Nfn13 78.2 14.3 1.3 145.6 0.1 K179.6 3.6 75.7 K1.3 K178.5 4.8
Nfn14 77.9 11.1 1.2 146.1 0.2 K179.6 3.9 71.4 K1.1 K178.2 K2.4
Nfn15 78.0 13.7 1.1 145.7 0.4 K179.7 3.7 72.7 K1.2 K178.3 K8.8
Nfn16 77.9 9.2 0.1 146.5 0.5 K179.3 3.7 67.8 K0.9 K178.4 3.1
Nfn17 78.7 3.9 0.3 3.0 0.4 K179.2 K178.0 38.1 K0.8 0.9 K20.6
Nfn18 78.1 4.8 0.4 3.6 0.5 K178.3 K178.2 38.9 K0.3 1.1 K27.4
Nfn19 152.2 115.6 4.7 1.3 0.3 176.3 K175.3 179.3 K1.7 2.0 14.5
Nfn20 78.1 8.1 1.1 145.9 0.3 K179.2 67.9 67.9 K0.9 K179.0 K12.4
Nfn21 77.9 9.4 1.1 145.6 0.3 K179.7 68.1 68.1 K1.0 K178.5 K5.5
Nfn22 95.2 116.6 K2.1 0.6 K0.2 1.8 K0.7 K0.8 K178.8 179.5 K51.4
Nfn23 149.4 120.0 5.1 K1.3 K0.1 K1.7 0.2 9.8 179.1 179.1 K30.4
Nfn24 76.3 42.4 0.9 K0.8 K0.3 K2.8 0.3 K67.7 178.9 K178.6 K27.9
Nfn25 94.4 104.1 K2.1 K140.9 0.1 0.4 178.1 K0.3 K179.8 K0.5 K27.5
Nfn26 97.5 118.7 K3.1 K142.5 0.5 0.1 178.0 8.6 K179.9 K0.8 K76.6
Nfn27 156.6 K63.0 4.0 0.7 K0.1 K2.4 3.5 178.1 178.8 K178.2 K65.4
Nfn28 96.2 113.6 3.6 1.5 K0.7 4.1 K1.1 K3.6 K178.9 K179.5 K70.7
Nfn29 140.6 122.5 6.2 0.3 0.1 K2.3 2.4 10.3 179.0 K178.5 K54.4
Nfn30 146.8 117.2 5.1 152.8 0.0 K1.1 K174.3 10.3 179.6 3.4 K52.2
Nfn31 147.8 112.6 4.7 154.3 0.2 0.3 K175.0 K12.4 K179.0 2.6 K59.0
Nfn32 142.6 117.7 5.6 154.2 0.2 K1.1 K175.2 11.2 179.4 3.2 K66.1
Nfn33 146.7 117.5 4.1 151.9 0.2 K2.1 K174.8 10.5 179.5 3.0 K49.3
Nfn34 150.2 117.1 5.0 2.1 K0.3 K1.5 4.1 7.6 K179.9 K178.1 9.4
Nfn35 K77.6 165.7 K0.1 124.0 K1.0 K1.3 179.7 K36.9 179.9 K0.4 6.3
Nfn36 153.9 112.8 3.7 3.2 0.3 K1.6 5.4 1.1 179.8 K176.9 K4.1
Nfn37 144.5 117.9 5.5 151.4 0.0 K1.9 K176.3 11.4 179.5 2.2 K11.5
Nfn38 97.1 118.5 K3.9 K142.9 0.5 0.1 177.4 7.8 K179.9 K0.9 K25.8
Nfn39 145.1 117.7 5.5 151.0 0.0 K1.8 K176.4 11.2 179.7 2.1 K5.1
Nfn40 147.6 121.2 5.0 K148.8 K0.1 175.4 2.5 7.3 2.3 K178.9 K33.9
Nfn41 148.1 119.1 5.2 0.3 K0.1 K1.7 1.9 6.5 K179.8 K179.6 K40.3
Nfn42 149.0 117.4 4.5 0.7 0.5 K0.5 0.8 K10.4 K179.2 179.3 K47.4
Nfn43 110.8 K86.1 K5.1 K154.7 0.1 K2.3 177.9 163.7 179.3 K1.0 K18.5
Nfn44 110.6 K86.4 K5.0 K154.0 0.1 K2.2 178.1 163.4 179.3 K1.0 K11.8

the protonation effect of the nitrogen of DHP ring on the This class of DHP compounds were substituted at the
molecular conformation was studied. C-3 (–COOR1) and C-5 (–COO(CH2)nR2) position. The
synthesis and determination of the biological activity of
these compounds were reported by Miri and by the others
2. Materials and method [3–9]. The structure and activity of these compounds are
shown in Table 1.
All the computations were run on a Pentium IV We undertook a molecular mechanic/MMC, semi
personal computer (CPU at 2.6 GH) with the windows XP emperical/AM1 and ab initio studies to elucidate the
operating system. For the conformational study aimed at conformational properties of a group of DHPs. MMC and
establishing a relationship between structure properties AM1 calculations were performed by Hyperchem software
and biological activity of DHP derivatives, we selected (version 7.0, Hypercube, Inc.). The Polak–Ribier algorithm
4-(1-methyl-5 nitro-2-imidazolyl) dihidropyridines. with root mean squares gradient of 0.1 kcal/mol was
142 B. Hemmateenejad et al. / Journal of Molecular Structure: THEOCHEM 717 (2005) 139–152

Table 3
The distribution of the individual conformations (in percentage) obtained by different calculation methods

Method Phase Trans/Trans Trans/Cis Cis/Cis ap sp

Protonated AM1 Gas 6.81 61.36 31.81 45.45 54.54
MMC Gas 11.36 59.09 29.54 50.00 50.00
MMC Liquid 13.63 65.90 20.45 72.72 27.27
Non-protonated AM1 Gas 6.81 70.45 22.72 50.00 50.00
Ab initio Gas 88.63 11.36 0.00 11.36 88.63
MMC Gas 6.81 70.45 22.72 22.72 77.27
MMC Liquid 18.18 34.09 47.72 56.82 43.18

Table 4
In liquid phase optimized dihedral angles (8) and DHf (Kcal/mol) for the most stable conformers of the studied DHP derivatives obtained by molecular
mechanic/MMC calculation

Compound 1 0 -4-3-2 2 0 -1 0 -4-3 1-2-3-4 7-8-9-10 2-3-5-6 2-3-7-8 5-6-9-10 H4–CH3 4-3-7-8 4-5-9-10 DHf
Nfn1 94.1 47.3 K1.4 K151.6 K0.6 0.0 178.4 120.0 179.3 K1.7 K19.8
Nfn2 81.1 40.9 0.7 K144.5 0.0 1.5 179.6 64.8 K1.7 0.1 K56.6
Nfn3 98.7 58.8 K2.3 K154.8 K0.6 K0.9 177.8 143.5 K179.8 K1.7 K53.8
Nfn4 91.7 69.3 K1.2 K147.9 K0.3 0.9 178.4 107.2 K178.8 K1.9 K55.5
Nfn5 84.5 52.3 0.6 147.3 K0.8 K178.2 2.9 92.6 0.8 K178.8 K32.7
Nfn6 93.2 50.3 K0.9 150.3 K1.1 K178.9 0.7 128.9 0.1 K179.6 K38.4
Nfn7 80.0 33.2 0.5 150.1 K0.3 K177.1 5.0 71.0 0.4 K177.4 K41.9
Nfn8 88.8 46.5 K0.6 149.0 K0.4 K179.2 2.2 127.3 K0.4 K178.8 K44.0
Nfn9 109.8 92.1 K5.1 166.8 K0.7 179.5 4.4 166.4 2.7 K175.1 K53.7
Nfn10 91.3 43.0 K0.9 146.0 K1.0 K179.3 K1.7 134.4 K0.1 177.8 K33.9
Nfn11 93.2 46.4 K0.9 150.1 K0.8 179.8 2.0 124.0 K0.6 K178.5 18.2
Nfn12 90.9 48.6 K0.4 152.6 K2.0 179.6 5.0 123.1 K0.7 K174.9 13.5
Nfn13 91.9 50.7 K0.5 146.5 K1.1 179.2 0.2 135.6 0.6 K179.5 8.3
Nfn14 79.5 25.2 0.8 145.5 0.2 179.4 5.5 74.7 K1.0 K177.8 K1.8
Nfn15 88.3 32.9 K0.6 147.8 K1.0 K179.7 2.4 114.8 K0.5 K178.9 K3.1
Nfn16 81.2 35.5 0.4 147.5 0.1 K179.5 4.7 72.4 K1.6 K177.7 5.1
Nfn17 89.3 64.0 K1.9 0.4 0.4 K178.1 178.5 91.1 0.4 K1.6 K17.2
Nfn18 86.9 58.2 0.1 K1.6 K0.4 K178.4 177.4 92.2 K1.2 K1.6 K27.0
Nfn19 137.7 116.3 6.3 2.1 0.6 177.6 K176.3 177.8 K1.0 2.5 8.1
Nfn20 78.6 40.8 1.7 145.7 K0.5 K179.2 3.8 69.9 K1.5 K178.1 K9.3
Nfn21 94.1 45.3 K1.1 150.9 K1.4 179.0 3.6 125.9 K1.1 K177.6 K2.2
Nfn22 146.0 109.6 6.5 2.5 K0.3 K1.0 3.6 1.5 K179.8 K177.3 K39.5
Nfn23 142.2 115.1 5.5 1.4 0.6 K1.3 1.1 2.3 K179.3 K179.1 K33.6
Nfn24 78.5 48.3 K0.4 0.4 0.0 K3.7 2.3 K71.6 178.6 K176.8 K26.5
Nfn25 96.5 115.6 K4.2 K148.7 0.2 K1.7 176.3 K6.6 179.3 K1.7 K27.9
Nfn26 101.1 122.1 K7.5 K146.1 2.4 K0.8 177.7 4.3 K179.4 1.2 K74.2
Nfn27 111.9 K107.3 K5.6 K3.7 K0.2 K4.2 0.3 147.4 178.5 179.2 K62.2
Nfn28 96.1 122.3 K3.6 K1.2 K0.1 K0.7 K1.0 K3.7 179.6 179.3 K32.6
Nfn29 155.3 114.7 6.8 K4.9 K2.2 K3.2 0.8 10.1 178.2 177.7 K46.2
Nfn30 144.0 111.9 5.3 155.9 1.0 K2.6 K173.1 K2.4 178.1 5.9 K52.8
Nfn31 144.8 111.1 5.4 156.5 0.4 0.8 K176.6 0.9 K178.1 2.8 K60.3
Nfn32 145.5 114.9 4.7 155.0 0.4 K1.9 K174.5 9.4 179.6 2.7 K64.1
Nfn33 137.9 60.1 K3.3 155.6 0.0 K6.2 K179.9 K47.3 180.0 1.9 K50.7
Nfn34 137.4 60.0 K3.2 0.0 0.0 1.6 0.0 K47.4 180.0 180.0 K35.7
Nfn35 99.7 62.9 K2.2 K155.1 K0.9 K0.3 177.0 146.4 K178.8 K2.6 10.0
Nfn36 91.6 51.6 0.4 147.1 K1.8 180.0 1.1 134.8 K0.4 K179.7 2.2
Nfn37 81.9 22.5 0.5 151.9 K0.2 K176.0 3.3 89.0 K1.1 K177.9 K4.9
Nfn38 86.2 45.4 K0.1 146.3 K0.8 179.7 1.7 115.3 0.0 K179.3 K11.2
Nfn39 82.9 32.1 0.2 149.0 K0.4 K176.8 3.0 92.3 0.7 K178.9 K1.3
Nfn40 94.5 55.6 K0.9 K5.4 K1.2 177.6 177.4 146.9 K1.5 K1.2 K20.8
Nfn41 87.9 61.3 0.0 K2.9 K0.6 K179.1 176.7 93.3 K1.8 K1.8 K2.2
Nfn42 92.3 49.4 K1.2 K2.0 K1.0 K177.9 178.4 133.7 0.7 K1.6 9.2
Nfn43 80.2 30.9 0.2 150.3 0.3 K176.8 4.5 70.3 0.5 K177.6 K15.7
Nfn44 95.5 56.0 K1.2 150.3 K1.3 179.9 1.9 135.2 0.1 K178.9 K8.0
 B. Hemmateenejad et al. / Journal of Molecular Structure: THEOCHEM 717 (2005) 139–152 143

selected for optimization. In order to prevent the structures 3. Results and discussion
locating at local minima, geometry optimization was run
many times with different starting points for each molecule. DHPs calcium channel modulators of nifedipine type
GAUSSIAN98 [31] was operated for ab initio calculations. The have been known to be flexible molecule. The aryl ring at
structures were optimized with 6-21G basis set for all atoms C-4 and ester groups at C-3 and C-5 can rotate so that the
at the RHF level. No molecular symmetry constraint was conformation of dihidropyridine ring changes. However,
applied, rather full optimization of all bond lengths and distinct local minima are found for geometries [32]. The
angles was carried out at the level RHF/6-21G. The ab initio basic chemical structure and numbering of the molecules
and AM1 calculations were run in the gas phase whereas are shown in Fig. 1. The most important conformational
MMC calculation were used to find the optimum features considered in this study are:
3D geometry of the molecules in both gas and aqueous cis or trans orientation of carbonyl groups bonded at C3
phases. and C5; C2–C3–C7–O8 (a1) and C5–C6–C9–O10 (a2)

Table 5
In gas phase optimized dihedral angles (8) and DHf (Kcal/mol) for the most stable conformers of the protonated form of DHP derivatives obtained by molecular
mechanic/MMC calculations

Compound 1 0 -4-3-2 2 0 -1 0 -4-3 1-2-3-4 7-8-9-10 2-3-5-6 2-3-7-8 5-6-9-10 H 4–CH3 4-3-7-8 4-5-9-10 DHf
Nfn1 118.1 99.6 K1.5 K176.6 0.6 K2.6 179.2 170.3 178.3 3.1 229.1
Nfn2 112.7 94.5 0.1 K170.3 K1.0 K0.3 177.9 167.0 179.5 1.4 197.0
Nfn3 115.8 99.5 K1.7 K173.5 0.3 K2.9 178.2 171.4 177.7 K0.1 227.0
Nfn4 132.7 115.7 1.9 K1.2 K0.3 177.6 K178.8 K179.9 K0.7 0.0 192.9
Nfn5 155.6 114.2 7.7 K153.1 0.0 177.5 4.9 177.8 K0.9 K176.0 226.6
Nfn6 152.2 120.5 8.2 K161.1 0.7 177.0 K0.7 K176.0 K1.4 178.9 217.8
Nfn7 159.1 116.9 7.4 K155.8 K0.8 177.0 2.9 179.1 K1.0 K178.9 213.5
Nfn8 154.3 116.5 8.3 K157.6 K0.1 176.5 2.8 177.0 K1.3 K178.8 207.9
Nfn9 153.8 117.4 7.6 K155.9 0.5 177.9 2.2 177.5 K0.9 K178.8 200.1
Nfn10 148.7 119.5 9.3 K160.5 0.6 177.5 0.1 178.1 K1.4 K179.7 217.8
Nfn11 158.4 116.7 6.9 K155.3 0.1 177.3 2.8 178.3 K1.1 K179.3 281.9
Nfn12 153.5 117.4 8.6 K158.3 K0.1 177.8 1.4 177.9 0.0 K179.7 275.4
Nfn13 157.9 117.4 7.1 K154.5 K0.2 177.9 2.6 178.8 K1.2 K178.9 267.5
Nfn14 163.3 115.3 2.6 K3.5 K0.3 K6.2 3.5 179.5 177.3 K179.5 250.7
Nfn15 160.9 116.0 2.2 K1.7 0.8 K6.4 4.1 K179.5 176.8 K178.4 235.8
Nfn16 151.4 122.0 9.1 K159.0 K0.4 177.3 1.4 K176.8 K1.3 K179.4 262.9
Nfn17 119.7 122.3 0.1 0.0 K0.3 K179.5 179.8 K176.3 0.0 1.6 222.7
Nfn18 136.4 114.3 1.6 K0.4 0.5 178.2 K179.2 177.5 K0.5 0.3 217.6
Nfn19 147.7 115.9 10.0 5.0 K1.3 177.7 K171.0 K179.0 K0.8 7.0 270.7
Nfn20 145.6 114.4 2.1 K4.4 0.1 K5.7 2.9 178.1 176.8 K179.7 227.8
Nfn21 158.7 116.1 4.6 K155.4 K0.3 176.0 3.9 179.0 K1.2 K178.8 236.2
Nfn22 143.6 117.4 3.2 K0.8 0.1 K3.1 2.5 K5.9 179.6 179.5 128.5
Nfn23 140.8 117.4 3.0 K2.1 0.3 K3.2 1.0 K5.1 179.4 178.8 136.8
Nfn24 89.9 104.6 0.1 1.2 K1.5 2.6 K0.1 K11.1 K179.3 K178.6 123.7
Nfn25 92.0 109.8 K0.9 K1.3 K0.6 K177.5 176.8 K6.2 0.3 K0.6 138.6
Nfn26 91.3 109.4 K0.8 K136.2 K0.4 3.0 177.0 1.0 K179.0 K0.3 88.5
Nfn27 118.4 K77.4 K0.5 2.0 K0.6 0.1 2.1 160.6 180.0 K178.1 105.5
Nfn28 141.2 117.5 2.9 K2.0 0.3 K3.2 1.1 K5.3 179.4 178.8 122.7
Nfn29 90.2 108.2 K0.3 2.2 K1.1 2.8 0.6 K47.2 K179.2 K178.1 103.1
Nfn30 91.4 110.0 K0.9 K133.4 0.8 3.0 179.8 1.5 K179.0 1.5 101.7
Nfn31 91.1 106.4 K0.9 K131.3 K0.1 3.7 179.1 0.6 K178.6 K0.4 98.0
Nfn32 91.4 110.3 K1.0 K134.8 K0.5 3.0 178.2 1.2 K179.0 0.3 89.4
Nfn33 91.8 112.3 K1.2 K131.7 K0.2 2.8 179.8 3.9 K179.1 0.2 105.2
Nfn34 92.2 123.4 K0.7 K2.0 K0.1 3.5 K5.4 K1.9 K178.4 176.8 161.5
Nfn35 K84.2 K93.5 K1.7 127.8 1.0 K4.2 K178.1 14.7 177.2 0.1 157.4
Nfn36 83.5 89.7 1.2 K2.1 K1.2 1.9 K7.8 K15.2 K179.6 171.6 162.1
Nfn37 150.1 114.6 3.4 146.7 0.3 K2.6 K176.7 K9.2 180.0 1.3 162.3
Nfn38 91.3 110.2 K0.9 K135.4 K0.3 3.0 177.3 1.6 K179.0 K0.3 137.5
Nfn39 91.9 111.0 K1.3 K133.9 K0.2 3.3 178.3 5.0 K178.8 0.2 148.7
Nfn40 75.4 64.3 3.2 119.6 K1.5 178.9 K1.7 K33.4 K0.8 179.8 137.5
Nfn41 135.9 118.8 2.1 K1.6 0.1 K2.7 1.4 K5.0 179.5 179.1 131.4
Nfn42 132.8 115.1 1.9 1.0 K0.1 K1.3 2.7 K8.6 K179.5 K179.7 121.4
Nfn43 79.2 169.3 K0.2 K120.7 1.2 2.4 K179.1 29.9 K179.4 0.9 139.8
Nfn44 78.9 170.7 K0.1 K120.0 1.3 2.3 K178.6 30.6 K179.4 1.1 147.3
144 B. Hemmateenejad et al. / Journal of Molecular Structure: THEOCHEM 717 (2005) 139–152

dihedral angles reflect it. If these angles were between K908 The relative position of nitroimidazolyl ring with respect to
and C908, the orientation was considered cis, and the trans DHP ring as measured by N1–C4–C3–C2 (a3) dihedral angle.
orientation was assumed when the dihedral angels were The deviation from planarity of DHP ring as measured by
between (C908)K(C1808) or (K908)K(K1808). The C2–C3–C5–C6 (a4) dihedral angle.
molecules were assigned as cis–cis, cis–trans, and trans– Molecular mechanic (MMC), semi empirical (AM1)
trans based on orientation of the individual carbonyl groups. and ab initio calculation methods were employed to find the
The orientation of the methyl of the nitroimidazolyl ring optimum values of the conformational features mentioned
with respect to the hydrogen atom bonded at C4; If the above. Gas phase calculation was performed by all methods,
methyl group was oriented in the same direction of the while; only MMC was operated for aqueous phase
hydrogen (i.e. out of the plane of the DHP ring) calculations. Because the DHP ring had a basic nitrogen
the conformation was assigned syn-periplanar (sp) and and it might be protonated at the physiological pH,
otherwise the conformation was named anti-periplanar (ap). AM1 and MMC was conducted on the neutral as well as

Table 6
In liquid phase optimized dihedral angles (8) and DHf (Kcal/mol) for the most stable conformers of the protonated form of DHP derivatives obtained by
molecular mechanic/MMC calculations

Compound 1 0 -4-3-2 2 0 -1 0 -4-3 1-2-3-4 7-8-9-10 2-3-5-6 2-3-7-8 5-6-9-10 H4–CH3 4-3-7-8 4-5-9-10 DHf
Nfn1 79.8 38.8 K18.3 142.3 0.7 K6.7 K178.6 90.5 178.9 K3.6 244.0
Nfn2 112.3 98.2 K0.1 K167.4 K0.5 0.8 176.7 169.5 K179.4 K0.7 181.7
Nfn3 108.0 90.5 K1.7 K160.2 0.3 0.3 179.4 176.5 K179.9 1.0 201.7
Nfn4 126.3 113.1 K1.7 3.8 1.0 179.8 K176.5 177.2 K0.3 2.5 197.4
Nfn5 95.0 15.3 26.0 157.0 0.7 K177.7 K3.1 100.1 K177.7 K3.1 238.9
Nfn6 159.4 117.4 4.9 K158.9 K1.0 175.6 2.6 K177.4 K1.3 180.0 207.1
Nfn7 168.4 118.1 6.8 K159.4 K3.5 176.5 0.5 K171.5 K1.4 176.8 200.9
Nfn8 136.4 118.1 12.2 K168.5 1.0 177.5 K1.3 176.5 K0.7 K179.9 210.0
Nfn9 153.4 116.9 8.4 K160.2 0.0 176.0 1.1 178.6 K1.9 K179.7 200.1
Nfn10 142.5 116.2 10.0 K167.5 2.0 177.8 K1.8 176.0 1.0 178.4 219.9
Nfn11 133.2 112.8 14.9 K174.1 K0.1 177.2 K1.6 172.7 0.2 179.3 285.4
Nfn12 132.6 113.4 12.3 K173.4 2.0 177.6 K2.7 170.8 0.6 179.0 279.7
Nfn13 128.6 113.5 14.5 K178.7 1.0 177.3 K3.5 174.3 K0.5 178.1 274.5
Nfn14 147.5 113.4 4.8 1.3 K0.5 K0.3 1.9 175.6 K177.8 178.8 257.0
Nfn15 151.5 114.2 4.9 K1.9 K1.9 K1.9 5.4 179.9 K179.2 K178.5 234.8
Nfn16 88.0 34.3 K8.7 149.2 K1.3 179.6 6.3 103.5 K0.3 K177.5 264.7
Nfn17 126.4 113.2 0.9 K2.8 K0.9 179.2 178.6 175.5 1.1 K0.4 221.1
Nfn18 121.0 109.7 K0.9 K2.8 0.1 178.7 177.9 175.3 0.4 K0.1 219.3
Nfn19 142.5 116.9 11.1 2.6 0.6 177.4 K175.8 177.6 K1.3 3.4 262.4
Nfn20 129.1 117.5 K1.6 0.8 0.4 K3.6 4.0 K177.1 177.7 K177.5 227.3
Nfn21 155.0 109.4 2.8 K154.4 0.3 177.0 6.6 173.8 K0.1 K176.8 235.8
Nfn22 76.8 73.1 3.4 K5.2 K1.7 K2.0 K3.7 1.5 177.7 177.7 118.7
Nfn23 137.5 114.9 1.5 1.1 1.1 K2.7 1.8 2.3 K179.1 K179.4 135.8
Nfn24 76.0 66.3 2.9 K2.4 K1.7 K1.7 K1.2 K71.6 179.2 179.3 143.7
Nfn25 74.0 49.4 4.2 K3.7 K2.2 K179.7 178.6 K6.6 K1.2 0.5 152.0
Nfn26 159.8 61.0 3.4 129.9 0.0 7.7 180.0 4.3 K180.0 K5.1 113.4
Nfn27 K160.8 K133.5 0.7 0.6 K0.4 0.9 2.6 147.4 179.0 K179.0 104.0
Nfn28 92.5 124.2 K0.7 2.2 K0.9 3.3 K0.1 K3.7 K178.8 K179.8 108.9
Nfn29 140.2 113.3 5.8 K3.2 K2.2 K2.8 2.0 10.1 179.2 178.5 118.8
Nfn30 78.6 74.2 2.4 K135.2 K2.9 K2.6 179.7 K2.4 177.1 0.7 108.2
Nfn31 74.3 57.7 2.8 K126.4 K1.2 K1.4 179.4 K47.4 179.2 1.0 107.4
Nfn32 141.3 114.6 5.1 158.2 K0.8 K1.7 K175.3 9.4 K179.1 1.9 106.4
Nfn33 72.7 52.9 3.7 K125.5 K1.3 K2.7 179.0 K8.8 179.4 0.6 114.6
Nfn34 140.4 112.4 1.8 3.9 1.7 K1.7 3.6 K16.0 K179.0 K177.7 175.1
Nfn35 161.9 109.4 3.8 K152.4 K0.5 176.9 6.1 K179.9 K0.2 K177.3 252.4
Nfn36 163.6 111.3 4.4 K151.1 K1.7 178.1 6.9 179.3 0.5 K176.8 247.1
Nfn37 153.3 110.0 4.6 K164.0 K1.1 174.2 3.8 169.1 K1.7 K180.0 241.6
Nfn38 158.9 116.4 4.9 K159.6 K1.8 173.6 4.1 K175.9 K3.2 K179.2 169.0
Nfn39 160.8 113.4 3.8 K153.5 K0.7 176.0 6.6 K179.3 K0.9 K177.3 239.7
Nfn40 157.5 113.1 3.8 0.3 K0.1 176.3 K175.5 179.0 K1.1 1.8 207.8
Nfn41 149.1 114.0 2.8 2.4 1.2 178.7 K177.3 176.4 0.6 2.5 205.6
Nfn42 155.8 112.7 4.6 3.2 K1.2 176.1 K171.3 175.4 K0.7 4.8 160.0
Nfn43 161.8 111.3 3.6 K154.5 K0.1 176.4 5.6 178.5 0.9 K178.2 226.4
Nfn44 159.5 116.2 3.7 K158.1 K0.3 174.8 4.1 178.8 K1.2 K179.3 231.5
 B. Hemmateenejad et al. / Journal of Molecular Structure: THEOCHEM 717 (2005) 139–152 145

the protonated form of the molecules. In the protonated indicated that MMC calculations produced a flattened-boat
form, a HC ion was added to the nitrogen of DHP and conformation with a nitroimidazolyl aromatic substituent in
therefore, it was considered as quaternary ammonium ion. its pseudo-axial position. The resulted conformation of most
The computed values of the relevant dihedral angels of the DHP derivatives (70.4%) in the gas phase was cis–
together with the corresponding enthalpy of formation trans or trans–cis whereas the conformation of 6.8% of the
(DHf) for the most stable conformer of each compound by molecules was cis–cis and that of the reminders (22.7%)
different method are listed in Tables 2–9. was trans–trans (Table 3). The conformation of the methyl
of the nitroimidazolyl ring with respect to the hydrogen
3.1. Molecular mechanic calculations attached to the C-4 was dependent on the type of R1
substituents (Table 1 and Fig. 1), so that 86.9% of the DHP
Conformational features of the DHP derivatives obtained derivatives, which their R1 was ethyl, showed sp confor-
by MMC calculations in the gas phase together with the mation, and all of the molecules, whose R1 was methyl,
enthalpy of formation (DHf) are listed in Table 2. The data took ap conformation.

Table 7
In gas phase optimized dihedral angles (8) and DHf (Kcal/mol) for the most stable conformers of the studied DHP derivatives obtained by semi empirical/AM1
calculations

Compound 1 0 -4-3-2 2 0 -1 0 -4-3 1-2-3-4 7-8-9-10 2-3-5-6 2-3-7-8 5-6-9-10 H 4 –CH3 4-3-7-8 4-5-9-10 DHf
Nfn1 105.0 61.7 6.9 174.3 K1.6 K25.9 K155.3 117.0 153.7 20.4 K90.6
Nfn2 105.7 59.1 5.5 143.1 K1.2 K35.7 K159.9 112.5 143.9 15.4 K129.4
Nfn3 106.2 58.8 5.3 141.8 K1.1 K36.3 K159.9 112.9 143.4 15.4 K128.8
Nfn4 105.6 58.7 5.4 145.8 K1.2 K34.6 K159.5 112.4 144.9 15.8 K125.5
Nfn5 95.7 30.4 8.2 138.3 K0.1 158.6 11.1 84.4 K22.9 K173.3 K104.2
Nfn6 108.4 61.9 4.3 94.3 K1.1 125.3 K7.0 115.4 K53.1 168.0 K112.0
Nfn7 104.9 49.9 4.8 122.0 K0.1 132.8 8.5 102.9 K46.0 K174.9 K117.5
Nfn8 104.2 48.7 4.8 113.1 0.0 131.6 4.3 101.4 K47.3 K179.4 K124.1
Nfn9 105.1 48.9 4.3 119.1 0.3 130.2 7.8 101.6 K48.8 K175.9 K131.0
Nfn10 106.4 58.1 4.8 102.9 K0.9 130.3 K2.2 111.5 K48.3 173.1 K115.3
Nfn11 103.6 50.3 4.8 113.0 0.1 133.3 4.9 102.8 K45.2 K179.5 K52.0
Nfn12 105.5 50.6 4.8 114.4 K0.3 132.4 4.3 104.0 K46.3 K179.3 K59.7
Nfn13 103.3 49.9 5.1 112.4 0.0 131.7 4.2 102.0 K47.2 K179.6 K66.4
Nfn14 104.3 49.1 4.9 116.4 K0.1 134.2 4.9 102.0 K45.0 K178.9 K73.5
Nfn15 105.9 50.3 5.1 121.3 K0.3 135.6 6.5 103.3 K43.8 K177.1 K80.5
Nfn16 105.5 50.3 4.9 116.7 K0.3 133.4 5.1 103.7 K45.5 K178.6 K67.4
Nfn17 104.9 54.5 5.4 K37.0 K0.2 127.6 K174.0 106.9 K51.1 2.1 K102.2
Nfn18 104.5 56.8 5.0 K28.4 0.4 128.3 K163.5 109.6 K50.2 11.8 K109.5
Nfn19 121.1 115.9 K1.0 26.8 K1.2 138.9 K105.8 179.0 K36.0 68.7 K72.2
Nfn20 104.7 49.8 4.8 118.5 K0.1 131.8 7.4 102.7 K46.9 K176.2 K82.3
Nfn21 104.8 50.1 4.8 112.5 K0.2 131.0 4.4 103.5 K47.3 K179.3 K75.1
Nfn22 109.5 65.5 2.7 37.4 1.3 32.4 5.8 K46.1 K146.9 K173.2 K102.9
Nfn23 95.3 118.5 8.8 2.5 0.1 K0.7 2.5 K0.3 178.2 K176.5 K104.0
Nfn24 126.3 41.2 K2.8 61.3 2.4 25.8 20.7 K60.8 K156.6 K161.7 K102.9
Nfn25 99.2 122.0 7.8 K121.9 0.2 K2.3 K174.1 K47.3 176.5 6.6 K93.7
Nfn26 109.7 65.1 2.6 K85.4 1.2 32.0 K161.5 K46.2 K147.3 18.5 K131.8
Nfn27 119.0 K70.8 1.9 K30.1 K1.0 7.7 158.8 158.9 154.7 K176.2 K134.2
Nfn28 109.4 65.4 2.7 39.0 1.3 6.6 K46.2 K46.2 K146.5 K172.3 K107.3
Nfn29 107.8 65.2 3.2 31.3 1.2 2.3 K45.3 K45.4 K146.8 K177.6 K114.0
Nfn30 108.8 65.1 3.0 K90.7 1.2 K167.2 K45.0 K45.1 K149.1 12.6 K118.5
Nfn31 109.5 65.6 2.8 K89.4 1.2 K165.4 K45.6 K45.6 K149.0 14.7 K125.5
Nfn32 110.7 65.5 2.6 K86.5 1.1 K161.6 K46.5 K46.6 K148.0 19.1 K131.4
Nfn33 139.6 144.8 K2.1 K24.1 0.7 K150.5 K13.0 K13.0 K162.7 22.7 K84.6
Nfn34 109.2 65.0 2.9 36.2 1.2 4.9 K46.0 K46.0 K146.5 K173.9 K80.2
Nfn35 K98.4 K122.5 K7.9 114.7 K0.2 171.1 K3.7 K3.7 K177.8 K9.5 K72.9
Nfn36 149.0 137.4 K3.1 23.0 0.3 74.9 K21.3 K21.3 K166.1 K104.2 K95.2
Nfn37 109.8 65.2 2.8 K85.4 1.1 K161.1 K46.2 K46.2 K147.7 18.9 K75.6
Nfn38 109.5 65.3 2.7 K87.9 1.2 K164.5 K46.0 K46.0 K147.7 15.6 K83.3
Nfn39 140.0 144.9 K2.3 K23.2 0.6 K144.3 K13.5 K13.5 K162.9 28.7 K101.5
Nfn40 92.3 113.0 9.9 119.1 0.2 2.2 K5.3 K5.3 K0.3 K176.6 K116.0
Nfn41 110.7 65.8 2.9 32.1 0.9 3.0 K45.9 K45.9 K149.8 K175.4 K113.2
Nfn42 110.2 65.8 2.7 34.1 1.2 3.7 K46.2 K46.2 K148.1 K174.9 K120.8
Nfn43 122.8 K57.8 K1.0 K128.6 0.2 K107.6 81.5 81.5 163.5 69.2 K89.0
Nfn44 121.3 K59.8 0.0 K148.4 K0.4 K120.4 K172.7 K172.8 161.0 55.4 K81.6
146 B. Hemmateenejad et al. / Journal of Molecular Structure: THEOCHEM 717 (2005) 139–152

Table 8
In gas phase optimized dihedral angles (8) and DHf (Kcal/mol) for the most stable conformers of the protonated form of new DHP obtained by semi
empirical/AM1 calculations

Compound 1 0 -4-3-2 2 0 -1 0 -4-3 1-2-3-4 7-8-9-10 2-3-5-6 2-3-7-8 H4–CH3 4-3-7-8 4-5-9-10 DHf
Nfn1 107.1 57.4 18.7 K176.8 K7.3 K21.3 116.6 161.0 18.7 124.2
Nfn2 120.1 73.2 8.9 150.2 K4.6 K40.0 133.9 143.6 38.4 91.1
Nfn3 110.3 61.5 0.2 146.5 K2.5 K47.5 145.6 132.7 K129.8 93.4
Nfn4 144.4 115.1 K7.6 K1.3 K0.1 K154.2 K179.9 28.2 K28.9 103.0
Nfn5 96.1 19.1 21.8 158.7 K5.5 173.7 79.3 K6.4 K164.7 104.6
Nfn6 116.2 56.3 8.3 117.3 K2.6 136.1 115.2 K38.9 177.0 115.0
Nfn7 115.8 51.9 8.5 154.5 K2.5 137.0 112.0 K37.8 K163.4 108.7
Nfn8 115.9 50.3 8.4 145.0 K2.3 137.3 110.7 K37.9 K167.8 102.3
Nfn9 103.5 52.9 26.1 163.4 K12.3 163.4 111.7 K13.1 K160.6 78.9
Nfn10 114.9 53.1 9.0 126.2 K2.7 137.4 111.9 K37.7 K177.4 111.7
Nfn11 116.1 53.0 7.6 166.0 K2.1 136.6 113.3 K38.3 K158.6 187.2
Nfn12 109.7 51.1 11.0 131.9 K3.4 140.3 108.5 K36.0 K172.9 175.0
Nfn13 107.6 48.5 6.2 120.3 0.3 132.4 102.8 K45.2 K177.6 192.3
Nfn14 154.4 122.8 K1.6 46.7 0.9 K93.5 K170.4 88.7 K138.4 152.5
Nfn15 154.2 118.1 4.0 K5.7 K2.7 K6.5 K177.9 178.4 179.9 164.3
Nfn16 101.3 38.6 K3.0 100.4 4.6 138.1 96.5 K39.4 174.4 172.5
Nfn17 139.3 92.5 K1.6 K9.0 K0.8 K104.7 K149.3 76.8 K66.8 125.3
Nfn18 143.4 93.2 K0.9 K9.3 0.5 K111.5 K149.3 70.3 K64.9 115.9
Nfn19 136.3 137.4 K1.8 90.5 K0.8 K160.5 K147.8 27.7 84.8 142.3
Nfn20 154.0 125.1 K1.5 46.4 0.8 K92.5 K168.1 89.6 K123.4 143.1
Nfn21 168.9 65.0 K1.3 K134.6 K3.1 K110.1 115.2 69.7 150.8 145.1
Nfn22 100.4 63.7 K2.2 51.2 0.4 54.3 K47.1 180.0 180.0 68.1
Nfn23 86.0 119.9 0.4 4.0 0.1 5.1 K0.2 K175.6 179.1 66.8
Nfn24 159.8 61.0 3.4 0.0 0.0 0.0 K1.5 K180.0 180.0 79.5
Nfn25 86.6 121.8 K0.7 K114.8 0.0 3.7 1.7 K176.8 K0.8 101.6
Nfn26 81.9 60.5 4.0 K131.2 0.0 K1.9 19.7 180.0 K7.3 43.8
Nfn27 131.5 K88.5 K0.7 K10.5 K1.3 K65.6 121.5 116.2 K121.6 53.3
Nfn28 159.8 61.0 3.4 0.0 0.0 2.8 14.0 K180.0 180.0 66.9
Nfn29 99.1 63.8 K2.2 41.6 0.4 55.3 K45.7 K126.3 K178.8 62.0
Nfn30 99.6 64.2 K2.3 K71.7 0.2 52.7 K47.1 K128.6 15.7 37.0
Nfn31 87.2 122.9 K0.8 K90.1 K0.6 K0.3 2.2 179.6 25.3 29.0
Nfn32 86.4 122.5 K0.7 K111.4 0.2 5.3 2.4 K174.9 K0.7 57.4
Nfn33 85.1 122.8 0.0 K107.8 K0.4 9.7 3.0 K170.0 K5.7 107.2
Nfn34 85.9 120.5 K0.5 4.1 0.2 4.9 0.2 K175.1 K179.9 99.0
Nfn35 K86.9 K120.8 0.4 K5.9 0.4 K3.7 K0.4 176.8 176.4 108.4
Nfn36 86.3 120.4 K0.1 K6.6 K0.4 2.7 0.2 K177.8 169.9 86.0
Nfn37 86.1 122.3 K0.6 K116.9 0.1 4.2 2.5 K176.0 K5.5 79.0
Nfn38 86.1 122.3 K0.6 K117.3 0.1 4.2 2.5 K176.0 K5.7 92.5
Nfn39 85.4 122.9 K0.8 K120.4 0.2 K9.1 3.8 170.3 K5.5 62.1
Nfn40 86.6 110.8 K1.1 113.8 0.6 172.3 K8.5 K8.5 K173.5 51.6
Nfn41 85.1 122.6 0.4 K20.1 K0.4 K14.2 K0.2 165.8 174.4 44.2
Nfn42 85.3 130.0 K1.0 K0.3 0.9 K0.7 8.5 179.2 K179.0 77.2
Nfn43 85.6 123.6 K0.5 K108.6 0.3 8.3 2.9 K171.8 K2.5 84.5
Nfn44 85.3 123.5 0.0 K143.4 K0.2 K4.2 3.8 175.6 K17.2 84.5

The results of the MMC calculations for the DHP cis–trans and trans–trans conformations. In the aqueous
derivatives in the aqueous phase are represented in Table 4. phase, the population of the cis–cis (47.7%) and trans–trans
As seen, the aqueous phase molecular mechanic calcu- (18.2%) conformations was higher and that of trans–cis or
lations produced relatively the same conformation patterns cis–trans (34.1%) conformations was lower than those of
with respect to the gas phase calculations. The flattened- gas phase.
boat conformation, were obtained in aqueous phase for all of In order to investigate the effect of the protonation of the
the DHP derivatives except six of them (Nfn12, Nfn21, DHP derivatives on their 3D geometries, a HC ion was
Nfn26, Nfn29, Nfn36 and Nfn44). For these molecules, the added to the nitrogen of the DHP ring and the MMC
angle between two C–C double bonds of the DHP ring was calculation was run for the protonated DHP derivatives in
greater than one degree. However, the magnitude of this the gas and aqueous phases. The results are represented in
angle was not high to consider the twist-like conformation Tables 5 and 6. The protonated forms of these compound
for these molecules. Another difference between the gas and showed slight differences from non-protonated ones, but the
the aqueous phase results was the distribution of the cis–cis, protonated forms also had relatively the same pattern of
 B. Hemmateenejad et al. / Journal of Molecular Structure: THEOCHEM 717 (2005) 139–152 147

Table 9
In gas phase optimized dihedral angles (8) and DHf (Kcal/mol) for the most stable conformers of the studied DHP derivatives obtained by ab initio calculation

Compound 1 0 -4-3-2 2 0 -1 0 -4-3 1-2-3-4 7-8-9-10 2-3-5-6 2-3-7-8 5-6-9-10 H 4 –CH3 4-3-7-8 4-5-9-10 DHf
Nfn1 K95.9 61.4 K8.7 0.9 K0.1 176.8 K176.0 0.4 0.4 0.2 K53.2
Nfn2 K99.2 59.2 K8.5 K10.2 1.4 177.1 169.3 K0.8 0.3 K12.0 K93.3
Nfn3 K97.5 63.5 K8.9 K9.4 K0.3 178.6 172.3 0.9 0.6 0.7 K68.9
Nfn4 K96.7 66.4 K9.3 0.3 K0.1 K173.2 K176.8 0.0 0.7 K0.7 K58.2
Nfn5 K84.8 90.9 K12.3 K124.7 1.1 K174.3 13.7 30.1 2.1 K173.2 K62.5
Nfn6 K95.2 64.3 K9.2 K152.3 0.3 177.6 4.0 3.9 0.6 179.6 K68.5
Nfn7 K112.7 K127.9 K1.7 K21.0 K0.5 K177.6 152.7 171.7 K0.2 K22.6 K62.1
Nfn8 K96.3 61.1 K8.7 K0.2 0.1 176.8 K177.1 0.0 0.4 K0.6 K78.9
Nfn9 K96.2 61.0 K8.7 0.0 0.0 176.8 K176.9 0.0 0.4 K0.5 K84.2
Nfn10 K96.5 61.0 K8.6 K1.1 0.2 176.8 K178.4 0.2 0.3 K1.9 K69.7
Nfn11 K113.4 K121.3 K1.4 K179.4 K0.9 K172.2 K14.0 175.5 4.3 168.4 K6.8
Nfn12 K99.1 65.5 K7.8 3.1 0.3 179.5 K175.9 1.7 1.4 K2.4 K19.3
Nfn13 K96.9 61.1 K8.6 K2.6 0.4 176.9 179.3 0.3 0.4 K3.7 K25.9
Nfn14 K95.9 61.3 K8.7 0.4 K0.1 176.8 K176.3 0.3 0.4 K0.2 K29.3
Nfn15 K94.3 62.3 K7.5 0.1 0.0 178.7 K177.5 0.4 0.5 K0.2 K31.2
Nfn16 K99.0 65.5 K7.8 3.1 0.3 179.5 K175.9 1.7 1.4 K2.3 K25.1
Nfn17 K95.9 61.5 K8.6 0.4 K0.3 177.0 K175.9 0.3 0.6 0.2 K57.7
Nfn18 K96.1 61.4 K8.6 0.2 K0.2 177.0 K176.4 0.3 0.5 K0.3 K65.1
Nfn19 K96.5 62.3 K8.8 1.1 0.0 177.6 K176.7 1.2 0.5 K0.4 K72.0
Nfn20 K96.4 61.1 K8.6 K0.5 0.1 176.8 K177.6 0.1 176.8 K177.6 K40.8
Nfn21 K95.9 61.5 K8.7 0.9 K0.1 176.9 K176.0 0.4 0.3 0.2 K58.1
Nfn22 K96.2 61.0 K8.6 0.0 0.0 176.9 K176.9 0.0 0.5 K71.9 K71.9
Nfn23 K97.3 64.0 K9.7 0.1 0.2 175.5 K176.5 K0.1 0.5 K65.7 K65.7
Nfn24 K96.1 61.1 K8.7 0.0 0.0 176.7 K176.8 K0.1 0.4 K34.1 K34.1
Nfn25 K96.3 61.0 K8.6 0.0 0.0 K176.7 176.9 0.0 0.5 K50.6 K50.5
Nfn26 K99.2 59.2 K8.4 K10.1 1.3 177.2 169.3 K0.7 0.5 K98.4 K98.4
Nfn27 K99.1 59.3 K8.5 K9.7 1.3 177.3 169.8 K0.7 0.6 K92.9 K92.9
Nfn28 K98.1 62.5 K7.4 K20.6 K0.6 K176.4 175.4 K2.6 2.9 K88.9 K88.9
Nfn29 K114.1 K121.6 K1.8 177.0 K0.6 K174.5 K13.4 175.7 2.1 K65.6 K65.6
Nfn30 K112.8 K128.2 K1.2 K20.0 K0.7 K175.5 152.6 171.5 1.8 K65.7 K65.7
Nfn31 K96.3 61.0 K8.6 K0.1 0.0 176.9 K177.0 0.0 0.5 K83.9 K83.8
Nfn32 K96.2 61.0 K8.6 0.0 0.0 176.9 K176.8 0.0 0.5 K89.5 K89.4
Nfn33 K96.5 61.1 K8.6 K1.0 0.1 177.0 K178.4 0.2 0.5 K74.6 K74.6
Nfn34 K94.7 64.5 K9.3 K153.6 0.3 178.4 2.2 3.7 1.3 K21.0 K20.9
Nfn35 K99.1 65.5 K7.8 3.1 0.2 179.7 K176.0 1.7 1.5 K24.3 K24.2
Nfn36 K97.1 67.9 K8.5 4.5 K0.2 178.4 K174.5 3.6 3.6 K32.5 K27.7
Nfn37 K96.0 61.3 K8.6 0.4 K0.1 176.9 K176.3 0.3 0.5 K34.2 K34.1
Nfn38 K112.9 K116.7 K2.2 K1.1 0.0 K167.3 166.1 179.7 8.9 K29.8 K29.7
Nfn39 K99.0 65.5 K7.8 3.1 0.2 179.6 K175.9 1.6 1.5 K30.3 K33.9
Nfn40 K95.9 61.4 K8.5 0.5 K0.4 177.1 K175.8 0.2 0.7 K63.1 K63.0
Nfn41 K96.5 62.3 K8.7 1.3 0.0 177.6 K176.3 1.2 0.5 K70.9 K70.8
Nfn42 K96.1 61.3 K8.6 0.1 K0.2 177.0 K176.6 0.3 0.6 K76.1 K76.0
Nfn43 K96.4 61.0 K8.6 K0.6 0.1 176.9 K177.6 0.0 176.9 K45.7 K45.6
Nfn44 K96.1 61.0 K8.7 0.1 0.0 176.9 K176.8 K0.1 0.5 K38.8 K38.8

orientation in both gas and water. The data shown in The plots of the calculated enthalpy of formation by the
Tables 5 and 6 indicated that the deviation of the boat-like MMC method in the aqueous phase against the gas phase
conformer of the protonated DHP’s from the planarity was are shown in Fig. 3. As it is observed, there is a good
more than that of non-protonated molecules. The calculated correlation between the calculated values DHf in the
improper dihedral angle between the C–C double bonds of aqueous and gas phase for the non protonated molecules.
the DHP ring was greater than one degree for about 20 and However, this correlation for the protonated DHP’s,
50% of the protonated DHP’s in the gas and aqueous phases, especially those molecules with R1Zethyl, is poor.
respectively. The largest value of this improper dihedral
angle was about 4.08 Therefore, it could be concluded that 3.2. Semi empirical calculations
MMC calculation predicted a twist-like conformer for
some of the DHP derivatives used in this study. As an Semi empirical calculations were carried out by AM1
example, the calculated 3D geometry by MMC in the gas Hamiltonian. This Hamiltonian was previously employed
and aqueous phases are shown in Fig. 2 for Nfn7 and Nfn27. by the other authors to study the other types of DHP
148 B. Hemmateenejad et al. / Journal of Molecular Structure: THEOCHEM 717 (2005) 139–152

Fig. 2. The optimized 3D structures of the Nfn2 (left side) and Nfn26 (Right side) obtained by MMC method. The upper to lower structures are in gas phase, in
liquid phase, in gas phase-protonated and in liquid phase-protonated, respectively.

Fig. 3. Plots of calculated heat of formation in aqueous phase against the gas phase by MMC method for the non-protonated (A) and protonated (B) molecules.
 B. Hemmateenejad et al. / Journal of Molecular Structure: THEOCHEM 717 (2005) 139–152 149

derivatives [21,32]. AM1 calculation was carried out in the calculation produced lower deviation from planarity for the
gas phase for both the protonated and non-protonated protonated molecules. Both the ap and sp configurations
molecules. The results are listed in Tables 7 and 8. The were resulted for the methyl of the nitroimidazolyl aromatic
results were relatively similar to those obtained by MMC ring of both the protonated and the non-protonated DHP
calculations. The data revealed that AM1 calculations derivatives. Most of the DHPs (70.4% of the non-protonated
produced the boat-like conformations for all of the non- and 61.4% of the protonated molecules) preferred the cis–
protonated molecules. However, the boat conformation of trans or trans–cis conformation by AM1 calculation. The
about 43% of the studied molecules showed slight deviation 3D representations of some DHP derivatives obtained by
from the planarity. The dihedral angel between the C–C AM1 calculation are shown in Fig. 4. As observed, the
double bonds of the DHP ring of Nfn 24, which had greater protonation of the nitrogen of DHP ring did not significantly
deviation from planarity, was equal to 2.48. On the other affect the conformation of the molecules. The enthalpies
hand, unlike the molecular mechanic calculations, AM1 of the formation (as a criterion for the relative stability) of

Fig. 4. The optimized 3D structures of the protonated (left side) and non-protonated (right side) of some DHP derivatives obtained by AM1 calculations in the
gas phase. They are Nfn6, Nfn11, Nfn 23 and Nfn 40, respectively.
150 B. Hemmateenejad et al. / Journal of Molecular Structure: THEOCHEM 717 (2005) 139–152

The enthalpy of the formation resulted from the AM1 and

MMC methods, in gas phase, are compared in Fig. 5B and
5C. The data indicates that the calculated DHf of the
structures obtained by AM1 are lower than that obtained by
MMC. Thus, it can be concluded that AM1 resulted in more
stable 3D structures in relative to MMC. In addition, the
plots shown in Fig. 5B and C reveals that there is a linear
dependency between the results of AM1 and MMC.
Meanwhile, the correlation is higher for the non-protonated
DHPs in comparison with that of the protonated molecules.

3.3. Ab initio calculations

Needless to say, the ab initio calculations give more

accurate results in relative to the molecular mechanic and
semi empirical methods. However, these calculations
consume a large CPU time and therefore, their calculation
rate are very low. In our study, we employed RHF/6-21G
basis set, which had moderate accuracy in comparison with
the other basis sets. For simplicity, the ab initio calculations

Fig. 5. Plot of the calculated heat of formation by MMC for the protonated
DHPs against the non-protonated molecules (A) and plots of calculated heat
of formations obtained by AM1 against those obtained by MMC for the
non-protonated molecules (B) and protonated molecules (C).

the protonated and the non-protonated derivatives, obtained

by AM1 method, are listed in the last columns of the
Tables 7 and 8 and are plotted in Fig. 5A. Obviously,
the DHf of the protonated molecules are higher than that of
the non-protonated molecules. This confirms the lower
stability of the former. Fig. 5A shows a linear dependency
between the enthalpy of formations of the two types of the Fig. 6. The overlay 3D structures of some DHP derivatives for comparison
molecules. However, their correlation is not very high. of the calculation methods.
 B. Hemmateenejad et al. / Journal of Molecular Structure: THEOCHEM 717 (2005) 139–152 151

Acknowledgements

We are thankful to the Research Council of the Shiraz

University of Medical Sciences for financial support.

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