Design and synthesis of new 1,4-dihydropyridines containing 4(5)-chloro-5(4)-imidazolyl substituent as a novel calcium channel blocker

Article abstract of DOI:10.1007/s12272-011-0902-9

New analogues of nifedipine, in which the ortho-nitro phenyl group at position 4 has been replaced by 4(5)-chloro-5(4)-imidazolyl substituent and which are able to interact with the receptor by hydrogen binding were designed, synthesized, and evaluated as calcium channel antagonists. The designed dihydropyridines were synthesized using the Hantzsch condensation and evaluated as calcium channel antagonists using the high K+ contraction of guineapig ileal longitudinal smooth muscle. A docking study was performed using the AutoDock4 program, and QSAR equations were obtained using multilinear regression. Our computational studies indicated that the oxygen of the ester (O10) and the N3′ of the imidazole ring form a hydrogen bonding interaction with the NH of HIS 363 and NH of LYS354, respectively, and that the sum of the BEHp5 and RDF075p are the most significant descriptors. The results of calcium channel antagonist evaluation demonstrated that increasing the chain length in C3 and C5 ester substituents increased activity. The most potent compound was the bis-phenylpropyl ester (5l) derivative, in that it was more active than the reference drug nifedipine and that the bis-phenylethyl ester (5k) derivative had comparable activity with nifedipine. The present research revealed that the 4(5)-chloro-5(4)-imidazolyl moiety is a bioisoster of o-nitrophenyl in nifedipine and provided novel dihydropyridines with more activity as calcium channel antagonists.

Full text of DOI:10.1007/s12272-011-0902-9

Arch Pharm Res Vol 34, No 9, 1417-1426, 2011
DOI 10.1007/s12272-011-0902-9
Design and Synthesis of New 1,4-Dihydropyridines Containing 4(5)-
chloro-5(4)-imidazolyl Substituent as a Novel Calcium Channel
Blocker
Maryam Iman1, Asghar Davood2, Ali Reza Nematollahi2, Ahmad Rerza Dehpoor3, and Abbas Shafiee4
1Nanotechnology Research Center, Biotechnology Research Center, School of Pharmacy, Mashhad University of Medical
2
Sciences, Mashhad 91775, Iran, Department of Medicinal Chemistry, Pharmaceutical Sciences Branch, Islamic Azad
3
University, Tehran 19419, Iran, Department of Pharmacology, Faculty of Medicine, Tehran University of Medical Sci-
4
ences, Tehran 14174, Iran, Department of Medicinal Chemistry, Faculty of Pharmacy and Pharmaceutical Sciences
Research Center, Tehran University of Medical Sciences, Tehran 14174, Iran
(Received November 3, 2010/Revised February 16, 2011/March 16, 2011)
New analogues of nifedipine, in which the ortho-nitro phenyl group at position 4 has been
replaced by 4(5)-chloro-5(4)-imidazolyl substituent and which are able to interact with the
receptor by hydrogen binding were designed, synthesized, and evaluated as calcium channel
antagonists. The designed dihydropyridines were synthesized using the Hantzsch condensa-
tion and evaluated as calcium channel antagonists using the high K+ contraction of guinea-
pig ileal longitudinal smooth muscle. A docking study was performed using the AutoDock4
program, and QSAR equations were obtained using multilinear regression. Our computational
studies indicated that the oxygen of the ester (O10) and the N3' of the imidazole ring form a
hydrogen bonding interaction with the NH of HIS 363 and NH of LYS354, respectively, and
that the sum of the BEHp5 and RDF075p are the most significant descriptors. The results of
calcium channel antagonist evaluation demonstrated that increasing the chain length in C3
and C5 ester substituents increased activity. The most potent compound was the bis-phenyl-
propyl ester (5l) derivative, in that it was more active than the reference drug nifedipine and
that the bis-phenylethyl ester (5k) derivative had comparable activity with nifedipine. The
present research revealed that the 4(5)-chloro-5(4)-imidazolyl moiety is a bioisoster of o-nitro-
phenyl in nifedipine and provided novel dihydropyridines with more activity as calcium chan-
nel antagonists.
Key words: 1,4-dihydropyridines, Calcium channels antagonist activity, Quantitative struc-
ture-activity relationship, Imidazole
cardiac muscle contraction (Godfraind, 1986). The
Selected by Editors
discovery that the 1,4-dihydropyridine (DHP) class of
calcium channel antagonists inhibited the Ca+2 influx
represented a major therapeutic advance in the treat-
ment of cardiovascular disease such as hypertension,
INTRODUCTION
The influx of extracellular Ca+2 through L-type voltage angina pectoris, and other spastic smooth muscle
dependent calcium channels regulates a number of disorders (Fleckenstein, 1977). The DHP class of drugs,
important physiological functions, including smooth for which nifedipine is the prototype, has been the
subject of many structure activity relationship studies
Correspondence to: Asghar Davood, Department of Medicinal
Chemistry, Pharmaceutical Sciences Branch, Islamic Azad Uni-
versity, No 99, Yakhchal ave. Shariatie Street, Tehran 19419,
Iran
Tel: 98-21-2260-9043, Fax: 98-21-2260-2059
E-mail: adavood@iaups.ac.ir, adavood2001@yahoo.com
(Janis and Triggle, 1983). Changes in the substitution
pattern at the C3, C4, and C5 positions of DHPs alter
potency (Janis and Triggle, 1983; Coburn et al., 1988),
tissue selectivity (Schramm et al., 1983), and the con-
formation of the 1,4-DHP ring. One of the structural
1417

1418
M. Iman et al.
requirements is that the substituted aromatic ring root mean square gradient was 0.01 kcal/mol. Among
occupies an axial position perpendicularly bisecting all energy minima conformers, the global minimum of
the boat-like DHP ring with the substituent in a syn- two favored tautomeric forms of DHPs were compared
periplanar orientation (Davood et al., 2001, 2006, with the global minimum of nifedipine as a reference
2010). In previous studies, we reported that a C4 imid- drug. Thus, the superimposition of these conformers
azole substituent created active compounds as calcium were performed to confirm whether the tautomeric form
channel antagonist (Shafiee et al., 1996, 1998; Pourmorad could mimic the major conformation of the reference
et al., 1997; Davood et al., 2001). Herein, we describe drug to be used in the docking calculations. The re-
the synthesis and calcium channel antagonist activity sultant geometry was transferred into the Autodock
of new 1,4-dihydropyridines containing 4(5)-chloro-5(4)- (version 4) program package, and docking calculations
imidazolyl substituent. For selection of this hetero- were performed using Autodock tools. An L-type cal-
cycle substituent in the 4 position, the followings were cium channel, generated by resorting to multibody
considered:
molecular dynamics simulations, was downloaded from
1) Some heterocycle rings (imidazolyl moiety) were the PDB bank server (PDB entry 1T0 J).
effective as 4-aryl in dihydropyridine structure (Shafiee
et al., 1996, 1998; Davood et al., 2001).
Autodock 4 started with a ligand molecule in an
arbitrary conformation, orientation, and position and
2) Substitution of chlorine instead of NO2 in the 4- found favorable dockings in a protein-binding site using
aryl ring produced active compounds (Arrowsmith et both simulating annealing and genetic algorithms.
al., 1986).
AutoDockTools (ADT), which has been released as an
3) Considering the tatumeric forms (Fig. 1) of the extension suite to the Python Molecular Viewer, was
4(5)-chloro-5(4)-imidazolyl moiety, both of nitrogen used to prepare the protein and the ligand. For the
atoms probably can interact with the receptor by crystal structure of L-type calcium channel, polar
hydrogen binding (donor, acceptor) and so both of hydrogens were added, and then Kollman United Atom
tatumeric forms should be pharmacologically active. charges and atomic solvation parameters were assign-
Our molecular modeling studies in the gas and aque- ed. The grid maps of docking studies were computed
ous phases indicated that the 4-chloro tautomer had using AutoGrid 4 included in the Autodock4 distribu-
very good compatibility with the reference drug, nife- tion. Grid center was centered on the active site and
dipine, and was the main form and more stable than 60
the 5-chloro tautomer.
×
60
× 60 points with grid spacing of 0.375 were
calculated. The GA-LS method was adopted to perform
To rationalize these findings, we docked the com- the molecular docking. The parameters for GA were
pounds into the active site of an L-type calcium channel. defined as follows: a maximum number of 250,000
Furthermore, to obtain a quantitative understanding energy evaluations; a maximum number of genera-
of the structure activity relationships (SAR) of these tions of 27,000; mutation and crossover rates of 0.02
antagonists, a quantitative structure activity relation- and 0.8, respectively. Pseudo-Solis & Wets parameters
ships (QSAR) analysis was performed.
MATERIALS AND METHODS
Molecular modeling and docking studies
were used for local search and 300 iterations of Solis
& Wets local search were imposed. The number of
docking runs was set to 50.
Both Autogrid and Autodock computations were
performed on Cygwin. After docking, all the generated
The chemical structure of desired compounds was structures were assigned to clusters based on a toler-
determined using HYPERCHEM software (version7, ance of 1 Å all-atom RMSD from the lowest-energy
Hypercube Inc.). Conformational analysis of the de- structure. Hydrogen bonding and hydrophobic interac-
signed compounds in gas phase (Fig. 1A and B) and tions between docked potent agents and macromole-
aqueous solution (Fig. 1C and D), was performed using cules were analyzed using ADT (Version 1.5.2). The
HYPERCHEM through semi-empirical molecular or- conformation with the lowest (docked) energy was
bital (PM3) and molecular mechanic (MM+) calcula- considered to be the best docking result.
tion methods, respectively. The DHPs were placed in
the center of 48 water molecule periodic box with
dimensions of 12.0 by 10.0 by 12.0 and 2.3 Ångstroms
distance between the water and DHPs, to simulate
behavior in aqueous solution.
Computation of structural descriptors and de-
scriptive QSAR equation
QSAR have been widely used in the drug design
process whenever detailed structural information on
The molecular structures were optimized using the the ligand-receptor interactions have not been experi-
Polak-Ribiere (conjugate gradient) algorithm until the mentally available (Hansch and Fujita, 1964; Hansch,

Synthesis and Molecular Modeling of New Dihydropyridines
1419
Scheme 1. Synthesis of new 1,4-dihydropyridines containing 4-(5)-chloro-5(4)-imidazolyl substituent.
1969; Gaudio et al., 1994).
software was used to calculate different functional
Two-dimensional structures of molecules were drawn groups, topological, geometrical, and constitutional
using the Hyperchem 7.0 software. The final geom- descriptors for each molecule. Results based on the
etries were obtained with the semi-empirical PM3 docked conformations included the intermolecular en-
method in the Hyperchem program. The molecular ergy, Vdw-hb-desolv energy, electrostatic energy, total
structures were optimized using the Polak-Ribiere internal energy, torsional energy, unbound energy,
(conjugate gradient) algorithm until the root mean predicted binding energy, and inhibition_constant (Ki)
square gradient was 0.01 kcal/mol. The resulting geom- all of which we usedas descriptors in QSAR studies.
etry was transferred into the EDRAGON programs
The calculated descriptors were first analysed for
package (http://www.vcclab.org/lab/edragon). SPSS soft- the existance of constant or near-constant variables,
ware (version15) was used for the MLR regression and those detected were removed. In addition, to de-
analysis.
crease the redundancy existing in the descriptor data
A large number of molecular descriptors was calcu- matrix, the correlation of descriptors with each other
lated using Hyperchem, Dragon package and Autodock and with the activity (pIC50) of the molecules was
tools. Some chemical parameters including molecular examined and collinear descriptors (i.e. r > 0.9) were
volume (V), molecular surface area (SA), hydrophobi- detected. Among the collinear descriptors, the one that
city (LogP), hydration energy (HE), refractivity (Rf), had the highest correction with activity was retained
partial charge (PC), molecular polarizability (MP), and and the others were removed from the data matrix.
different quantum chemical descriptors including di- The calculated descriptors were collected in a data
pole moment (DM), local charges, HOMO, and LOMO matrix whose number of rows and columns were the
energies were calculated using Hyperchem. Dragon number of molecules and descriptors, respectively.

1420
M. Iman et al.
MLR with factor analysis as the data pre-processing
step for variable selection (FA-MLR) and principal
component regression analysis (PCRA) methods were
used to derive the QSAR equations.
General procedure for the prepartation of 3-
oxobutanoic acid esters (4c-l)
A solution of an alcohol and dioxin in xylene was
placed in an Erlenmeyer flask. The flask was immers-
ed in an oil bath that had been preheated to 150oC,
and the solution was vigorously stirred. The evolution
Chemistry
DHP’s agents (Table I) were synthesized according of acetone became apparent within several minutes
to Scheme 1 by using classical Hantzsch condensation and heating was continued from 1 to 3 h. The xylene
(Hantzsch, 1882; Goldmann and Stoltefuss, 1991) in was then removed, and the product was distilled.
which 4(5)-chloro-imidazole-5(4)-carboxaldehyde 3 was
reacted with 3-oxobutanoic acid ester 4a
nium acetate. Compound was prepared in three steps Using the general procedure and propyl alcohol
from formaldehyde, dihydroxyacetone, and ammonia provided the title compound after 2 h of reflux: Yield
(Davood et al., 2006). Some of the 3-oxobuthanoic acid 69%, bp 60-62oC/10 mmHg. IR (NaCl):
1747 (CO ester),
esters (4c 4.10 (t,
) were prepared according to the literature 1719 (CO, Ketone) cm−1. 1H-NMR (CDCl3):
(Li et al., 1998). = 6.5 Hz, 2H, OCH2), 3.45 (s, 2H, COCH2CO), 2.27 (s,
-l and ammo- Propyl 3-oxobutanoate (4c)
3
ν
-l
δ
J
Melting points were determined using a Thomas- 3H, CH3CO), 1.63 (m, 2H, CH2CH3), 0.88 (t,
Hoover capillary apparatus and were uncorrected. 1H- Hz, 3H, CH2CH3).
NMR spectra were recorded on a Bruker FT-500 spec-
J = 6.5
trometer TMS was used as an internal standard. In- Isopropyl 3-oxobutanoate (4d)
frared spectra were acquired on a Nicolet 550-FT spec- Using the general procedure and isopropyl alcohol
tometer. Mass spectra were measured with a Finnigan provided the title compound after 3 h of reflux: Yield
TSQ-70 spectrometer at 70 eV. Elemental analysis 55%. IR (NaCl):
ν
1745 (CO ester), 1715 (CO, Ketone)
was carried out with a Perkin-Elmer model 240-C ap- cm−1. H-NMR (CDCl3):
5.05 (m, 1H, C ), 3.42 (s,
paratus. The results of elemental analysis (C, H, N) 2H, COCH2CO), 2.2 (s, 3H, CH3CO), 1.25 (d, 6H,
1
δ
H
were within ± 0.4% of the calculated amounts.
CH3CHCH3).
4 (5)-hydroxymethylimidazole (1)
Isobutyl 3-oxobutanoate (4e)
This compound was prepared according to the litera- Using the general procedure and isobutyl alcohol
ture (Davood et al., 2006). mp 87-88oC; IR (KBr):
ν
provided the title compound after 2 h of reflux: Yield
1749 (CO
4.48
= 6.6 Hz, 2H, OCH2), 3.46 (s, 2H, COCH2CO), 2.16
1
3100 cm−1 (OH). H-NMR (DMSO-d6):
δ ν
4.43 (s, 2H, 80%, bp 70-72oC/10 mmHg. IR (NaCl):
CH2OH), 6.90 (s, 1H, H4 or H5-imidazole), 7.57 (s, 1H, ester), 1725 (CO, Ketone) cm−1. 1H-NMR (CDCl3):
H2-imidazole). Anal. Calcd. for C4H6N2O: C, 48.97; H, (d,
δ
J
6.16; N, 28.56. Found: C, 48.81; H, 6.07; N, 28.30.
(s, 3H, CH3CO), 2.48 (m, 1H, CH), 1.48 (d, J = 6.6 Hz,
6H, CH(CH3)2).
Imidazole-4(5)-carboxaldehyde (2)
This compound was prepared according to the litera- Cyclopentyl 3-oxobutanoate (4g)
ture (Davood et al., 2006). mp 146-147oC; IR (KBr):
ν
Using the general procedure and cyclopentyl alcohol
1665 cm−1 (CO). 1H-NMR (DMSO-d6):
δ 7.93 (s, 1H, H4 provided the title compound after 1 h of reflux: Yield
or H5-imidazole), 7.99 (s, 1H, H2, imidazole), 9.74 (s, 1H, 69%, bp 125-127oC/20 mmHg. IR (NaCl):
ν 1754 (CO
CHO), 12.98 (bs, 1H, NH). Anal. Calcd. for C4H4N2O: C, ester), 1727 (CO, Ketone) cm−1. H-NMR (CDCl3):
δ
1
50.00; H, 4.20; N, 29.15. Found: C, 50.28; H, 4.43; N, 5.30 (m, 1H, OCH), 3.41 (s, 2H, OCH2CO), 2.26 (s, 3H,
29.39.
CH3 CO), 1.70 (m, 8H, Cyclopentyl).
5(4)-chloroimidazole-4(5)-carboxaldehyde (3)
Cyclohexyl 3-oxobutanoate (4h)
This compound was prepared according to the litera- Using the general procedure and cyclohextyl alcohol
ture (Davood et al., 2006). mp 199-201oC; IR (KBr):
ν
provided the title compound after 2 h of reflux: Yield
1675 cm−1 (CO). 1H-NMR (DMSO-d6):
δ
7.98 (s, 1H, H2- 76%, bp 84-86oC/10 mmHg. IR (NaCl):
ν
1748 (CO
imidazole), 9.75 (s, 1H, CHO), 12.99 (bs, 1H, NH). 13C- ester), 1727 (CO, Ketone) cm−1. H-NMR (CDCl3):
δ
1
NMR (DMSO-d6): δ 185.98 (CO), 142.53 (C2, imidazole), 4.65 (m, 1H, OCH), 3.41 (s, 2H, OCH2CO), 2.26 (s, 3H,
139.59 (C5, imidazole), 126.68 (C4, imidazole). Anal. CH3 CO), 1.61 (m, 10H, Cyclohexyl).
Calcd. for C4H3ClN2O: C, 36.80; H, 2.31; N, 21.46.
Found: C, 36.64; H; 2.49; N, 21.29.

Synthesis and Molecular Modeling of New Dihydropyridines
1421
Cyclohexylmethyl 3-oxobutanoate (4i)
1H, NH). MS: m/z (%) 325 (M+, 3), 290 (100), 268 (5),
Using the general procedure and cyclohexylmethyl 223 (12), 191 (14), 132 (12), 59 (22). Anal. Calcd. for
alcohol provided the title compound after 2 h of reflux: C14H16ClN3O4: C, 51.62; H, 4.95; N, 12.90. Found: C,
Yield 79%, bp 81-83oC/50 mmHg. IR (NaCl):
ν
1740 51.44; H, 5.08; N, 12.75.
(CO ester), 1718 (CO, Ketone) cm−1. 1H-NMR (CDCl3):
3.95 (d, = 6.2 Hz, 2H, OCH2), 3.44 (s, 2H, OCH2CO), Diethyl 4-(4(5)-chloro-1H-imidazol-5(4)-yl)-2,6-di-
δ
J
2.27 (s, 3H, CH3CO), 1.46 (m, 11H, Cyclohexyl).
methyl-1,4-dihydropyridine-3,5-dicarboxylate (5b)
Using the general procedure and ethyl 3-oxobutanoate
provided the title compound after 48 h of reflux. The
Benzyl 3-oxobutanoate (4j)
Using the general procedure and benzyl alcohol solvent was removed under reduced pressure and the
provided the title compound after 2 h of reflux: Yield residue was purified by TLC (silicagel, chloroform-
84%. IR (NaCl):
ν 1755 (CO ester), 1732 (CO, Ketone) methanol = 20:1) and crystallized from diethyl ether
cm−1. 1H-NMR (CDCl3):
δ
7.45 (s, 5H, Phenyl), 5.30 (s, to give the title compound as a white crystals, yield
2H, OCH2), 3.6 (s, 2H, OCH2CO), 2.2 (s, 3H,CH3CO).
11%; mp > 300oC. IR (KBr):
(CO). H-NMR (CDCl3+DMSO-d6):
ν
3308 (NH), 1690 cm−1
1.22 (t, = 7.1
1
δ
J
Phenethyl 3-oxobutanoate (4k)
Hz, 6H, CH2CH3), 2.29 (s, 6H, C2, C6-CH3), 4.08 (q, J =
Using the general procedure and phenethyl alcohol 7.1 Hz, 4H, OCH2), 5.07 (s, 1H, H4-DHP), 7.23 (s, 1H,
provided the title compound after 2 h of reflux: Yeild H2-imidazole), 8.24 (bs, 1H, NH). MS: m/z (%) 323 (M+,
80%, bp 148-151oC/10 mmHg. IR (NaCl):
ν
1762 (CO 5), 323 (10), 318 (100), 307 (15), 280 (40), 234 (50), 224
(10), 196 (15). Anal. Calcd. for C16H20ClN3O4: C, 54.32;
1
ester), 1721 (CO, Ketone) cm−1. H-NMR (CDCl3):
δ
7.32 (s, 5H, Phenyl), 4.35 (t,
3.40 (s, 2H, OCH2CO), 2.95 (t,
2.20 (s, 3H, CH3CO).
J
J
= 6.5 Hz, 2H, OCH2), H, 5.70; N, 11.88. Found: C, 54.19; H, 5.85; N, 11.66.
= 6.5 Hz, 2H, CH2Ph),
Dipropyl 4-(4(5)-chloro-1H-imidazol-5(4)-yl)-2,6-di-
methyl-1,4-dihydropyridine-3,5-dicarboxylate (5c)
Phenpropyl 3-oxobutanoate (4l)
Using the general procedure and phenpropyl alcohol
Using the general procedure and propyl 3-oxobutanoate
(4c) provided the title compound after 48 h of reflux.
provided the title compound after 2 h of reflux: Yield The solvent was removed under reduced pressure and
87%, bp 169-172oC/10 mmHg. IR (NaCl):
1755 (CO the residue was purified by TLC (silicagel, chloroform-
ester), 1726 (CO, Ketone) cm−1. 1H-NMR (CDCl3):
7.26 methanol = 20:1) and crystallized from diethyl ether
(s, 5H, Phenyl), 4.16 (t, = 6.5 Hz, 2H, OCH2), 3.43 (s, to give the title compound as a white crystals, yield
= 6.5 Hz, 2H, CH2Ph), 2.33 (s, 50%; mp 201-203oC. IR (KBr): 3303 (NH), 1690 cm−1
(CO). H-NMR (CDCl3+DMSO-d6): 0.80 (t, = 6.97
ν
δ
J
2H, OCH2CO), 2.71 (t,
3H, CH3CO), 1.91 (m, 2H, CH2CH2Ph).
J
ν
1
δ
J
Hz, 6H, CH2CH3), 1.25-1.85 (m, 4H, CH2CH3), 2.22 (s,
6H, C2, C6-CH3), 3.92 (t, 4H, OCH2), 5.01 (s, 1H, H4-
DHP), 7.16 (s, 1H, H2-imidazole), 8.14 (s, 1H, NH-
DHP), 11.01 (bs, 1H, NH-imidazole). MS: m/z (%) 381
(M+, 6), 346 (100), 294 (42), 234 (87), 196 (42), 193
General procedure for preparation of dialkyl
(cycloalkyl, aryl) 4-(4(5)-chloro-1H-imidazol-5
(4)-yl)-2,6-dimethyl-1,4-dihydropyridine-3,5-di-
carboxylate (5a-l)
A solution of compound 3 (0.2 g, 1.5 mmol), ammo- (27), 149 (12), 43 (77). Anal. Calcd. for C18H24ClN3O4:
nium acetate (0.12 g, 1.5 mmol), and alkyl (cycloalkyl, C, 56.62; H, 6.34; N, 11.00. Found: C, 56.85; H, 6.37;
aryl) 3-oxobutanote (3 mmol) in methanol (3 mL) was N, 11.18.
refluxed. The solvent was removed under reduced
pressure and the residue was crystallized from di- Diisopropyl 4-(4(5)-chloro-1H-imidazol-5(4)-yl)-2,6-
ethylether to give the title compound.
dimethyl-1,4-dihydropyridine-3,5-dicarboxylate
(5d)
Dimethyl 4-(4(5)-chloro-1H-imidazol-5(4)-yl)-2,6- Using the general procedure and isopropyl 3-oxobu-
dimethyl-1,4-dihydropyridine-3,5-dicarboxylate
(5a)
tanoate (4d) provided the title compound after 48 h of
reflux. The solvent was removed under reduced pres-
Using the general procedure and methyl 3-oxobutano- sure and the residue was purified by TLC (silicagel,
ate provided the title compound after 48 h of reflux: chloroform-methanol = 20:1) and crystallized from
White crystals, yield 44%; mp > 300oC (diethyl ether). diethyl ether to give the title compound as a white
IR (KBr):
d6):
(s, 1H, H4-DHP), 7.45 (s, 1H, H2-imidazole), 8.21 (bs, 1.15 and 1.23 (dd,
ν
3395 (NH), 1716 cm−1 (CO). 1H-NMR (DMSO- crystals, yield 15%; mp 251-254oC. IR (KBr):
ν
3411
1
δ
2.26 (s, 6H, C2, C6-CH3), 3.64 (s, 6H, OCH3), 5.03 (NH), 1690 cm−1 (CO); H-NMR (CDCl3+DMSO-d6):
δ
J
= 6.28 Hz, 12H, CH(CH3)2), 2.28

1422
M. Iman et al.
1
(s, 6H, C2, C6-CH3), 4.78-5.22 (m, 3H, OCHand H4-DHP), (NH), 1736 (CO) cm−1. H-NMR (CDCl3+DMSO-d6):
δ
7.25 (s, 1H, H2-imidazole), 7.57 (s, 1H, NH-DHP), 10.31 1.67 (br, 16H, Cyclopentyl), 2.27 (s, 6H, C2, C6-CH3),
(bs, 1H, NH-imidazole). MS: m/z (%) 381 (M+, 2), 346 4.95-5.28 (m, 3H, H4-DHP and OCH), 7.24 (s, 1H, H2-
(13), 296 (60), 294 (33), 252 (17), 234 (12), 45 (72), 43 imidazole), 8.10 (bs, 1H, NH-DHP). MS: m/z (%) 433
(100). Anal. Calcd. for C18H24ClN3O4: C, 56.62; H, 6.34; (M+, 2), 399 (20), 398 (32), 348 (40), 296 (52), 252 (75),
N, 11.00. Found: C, 56.80; H, 6.12; N, 10.88.
196 (98), 178 (27), 151 (26), 106 (12), 69 (100). Anal.
Calcd. for C22H28ClN3O4: C, 60.89; H, 6.50; N, 9.68.
Diisobutyl 4-(4(5)-chloro-1H-imidazol-5(4)-yl)-2,6- Found: C, 61.02; H, 6.48; N, 9.81.
dimethyl-1,4-dihydropyridine-3,5-dicarboxylate
(5e)
Dicyclohexyl 4-(4(5)-chloro-1H-imidazol-5(4)-yl)-
Using the general procedure and isobutyl 3-oxobu- 2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxyl-
tanoate (4e) provided the title compound after 48 h of ate (5h)
reflux. The solvent was removed under reduced pres- Using the general procedure and cyclohexyl 3-oxobu-
sure and the residue was purified by TLC (silicagel, tanoate (4h) provided the title compound after 30 h of
chloroform-methanol = 18:1) and crystallized from reflux. The solvent was removed under reduced pres-
diethyl ether-petrolum ether to give the title compound sure and the residue was purified by TLC (silicagel,
as a white crystals, yield 30%; mp 151-152oC. IR (KBr): chloroform-methanol = 18:1) and crystalized from di-
ν
3272 (NH), 1705 cm−1 (CO); 1H-NMR (CDCl3):
(d,
2.31 (s, 6H, C2, C6-CH3), 3.88 (d,
δ
0.89 ethyl ether-petrolum ether to give the title compound
= 6.6 Hz, 12H, CH(CH3)2), 1.65-2.20 (m, 2H, CH), as a white crystals, yield 26%; mp: 148-151oC. IR (KBr):
= 6.11 Hz, 4H, OCH2), 0.98-
3293 (NH), 1675 (CO) cm−1. 1H-NMR (CDCl3):
J
J
ν
δ
5.12 (s, 1H, H4-DHP), 6.36 (s, 1H, NH-DHP), 7.26 pmm 2 (m, 20H, Cyclohexyl), 2.31 (s, 6H, C2, C6-CH3), 4.59-
(s, 1H, H2-imidazole). MS: m/z (%) 409 (M+, 1), 374 5.00 (m, 2H, OCH), 5.10 (s, 1H, H4-DHP), 6.2 (bs, 1H,
(100), 308 (35), 252 (17), 233 (75), 196 (50), 151 (15), 56 NH-DHP), 7.27 (s, 1H, H2-imidazole). MS: m/z (%) 461
(55), 41 (70). Anal. Calcd. for C20H28ClN3O4: C, 58.60; H, (M+, 1), 426 (25), 378 (22), 334 (46), 295 (27), 196 (30),
6.89; N, 10.25. Found: C, 58.86; H, 6.92; N, 10.49.
83 (65), 55 (100). Anal. Calcd. for C24H32ClN3O4: C,
62.40; H, 6.98; N, 9.10. Found: C, 62.54; H, 7.12; N,
Ditertiarybutyl 4-(4(5)-chloro-1H-imidazol-5(4)-yl)- 9.34.
2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxyl-
ate (5f)
Dicyclohexylmethyl 4-(4(5)-chloro-1H-imidazol-5
Using the general procedure and t-butyl 3-oxobutanoate (4)-yl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicar-
(4f) provided the title compound after 52 h of reflux. boxylate (5i)
The solvent was removed under reduced pressure and Using the general procedure and cyclohexylmethyl 3-
the residue was purified by TLC (silicagel, chloroform- oxobutanoate (4i) provided the title compound after 30
methanol = 18:1) and crystallized from diethyl ether- h of reflux. The solvent was removed under reduced
petrolum ether to give the title compound as a white pressure and the residue was purified by TLC (silica-
crystals, yield 20%; mp 232-234oC. IR (KBr):
ν 3419, gel, chloroform-methanol = 20:1) and crystallized from
1
3406 (NH), 1698 cm−1 (CO); H-NMR (CDCl3+DMSO- diethyl ether to give the title compound as a white
d6):
4.97 (s, 1H, H4-DHP), 7.26 (s, 1H, H2-imidazole), 7.92 3201 (NH), 1700 (CO) cm−1. 1H-NMR (CDCl3):
(s, 1H, NH-DHP), 10.13 (bs, 1H, NH-imidazole). Anal. (m, 22H, Cyclohexyl), 2.30 (s, 6H, C2, C6-CH3), 3.90 (d,
δ
1.46 (s, 18H, C(CH3)3), 2.27 (s, 6H, C2, C6-CH3), crystals, yield 27%; mp 194-196oC. IR (KBr):
ν
3283,
0.7-1.9
δ
Calcd. for C20H28ClN3O4: C, 58.60; H, 6.89; N, 10.25.
Found: C, 58.76; H, 6.62; N, 10.49.
J = 5.58 Hz, 4H, OCH2), 5.11 (s, 1H, H4-DHP), 6.6 (s,
1H, NH-DHP), 7.27 (s, 1H, H2-imidazole). MS: m/z (%)
489 (M+, 1), 455 (10), 454 (20), 348 (20), 252 (15), 234
Dicyclopentyl 4-(4(5)-chloro-1H-imidazol-5(4)-yl)- (20), 196 (17), 67 (10), 41 (100). Anal. Calcd. for
2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxyl- C26H36ClN3O4: C, 63.73; H, 7.40; N, 8.57. Found: C,
ate (5g)
63.50; H, 7.63; N, 8.75.
Using the general procedure and cyclopentyl 3-oxo-
butanoate (4g) provided the title compound after 36 h Dibenzyl 4-(4(5)-chloro-1H-imidazol-5(4)-yl)-2,6-
of reflux. The solvent was removed under reduced pres- dimethyl-1,4-dihydropyridine-3,5-dicarboxylate
sure and the residue was purified by TLC (silicagel, (5j)
chloroform-methanol = 19:1) and crystallized from Using the general procedure and benzyl 3-oxobutano-
diethylether to give the title compound as a white ate (4j) provided the title compound after 30 h of reflux.
crystals, yield 21%; mp 234-236oC. IR (KBr):
ν 3426 The solvent was removed under reduced pressure and

Synthesis and Molecular Modeling of New Dihydropyridines
1423
the residue was crystalized from diethyl ether to give a resting tension of 0.5 g. The segments were main-
the title compound as a white crystals, yield 28%; mp tained at 37C in a 20 mL jacketed organ bath contain-
1
81-83oC. IR (KBr):
NMR (CDCl3):
ν
3224 (NH), 1669 (CO) cm−1. H- ing oxygenated physiological saline solution of the
δ 2.28 (s, 6H, C2, C6-CH3), 5.08 (bs, 5H, following (mM) composition: NaCl, 137; CaCl2, 1.8;
H4-DHP, and OCH2Ph), 7.26 (s, 11H, H2-imidazole KCl, 2.7; MgSO4, 1.1; NaH2PO4, 0.4; NaHCO3, 12; and
and Phenyl); MS: m/z (%) 477 (M+, 1), 386 (27), 342 glucose, 5.
(10), 91(100), 65 (12). Anal. Calcd. for C26H24ClN3O4:
The muscles were equilibrated for 1h with a solution
C, 65.34; H, 5.06; N, 8.79. Found: C, 65.58; H, 5.30; N, change every 15 minutes, and the contraction was
8.93.
recorded with a force displacement transducer (F-50)
on a NARCO physiograph. Test agents were prepared
at 10-2 M stock solutions in dimethyl sulfoxide (DMSO)
and stored protected from light. Dilutions were made
in DMSO. The contractile response was taken as the
Diphenethyl4-(4(5)-chloro-1H-imidazol-5(4)-yl)-2,6-
dimethyl-1,4-dihydropyridine-3,5-dicarboxylate
(5k)
Using the general procedure and phenethyl 3-oxobu- 100% value for the tonic (slow) component of the
tanoate (4k) provided the title compound after 24 h of response. The contraction was elicited with 80 mM
reflux. The solvent was removed under reduced pres- KCl.Test compounds were cumulatively added and
sure and the residue was purified by TLC (silicagel, compound-induced relaxation of contracted muscle
chloroform-methanol = 20:1) and crystallized from was expressed as percent of control. The IC50 values
diethyl ether to give the title compound as a white (concentration needed to produce 50% relaxation on
crystals, yield 21%; mp 99-102oC (diethyl ether). IR contracted ileal smooth muscle) were graphically
(KBr):
2.20 (s, 6H, C2, C6-CH3), 2.91 (t,
4.14-4.48 (m, 4H, OCH2), 4.88 (s, 1H, H4-DHP), 6.18
ν
3288 (NH), 1705 (CO) cm−1. 1H-NMR (CDCl3):
= 6.6 Hz, 4H, CH2Ph), (Bolger et al., 1983; Rovnyak et al., 1992).
The research protocol and experimental animals were
δ
determined from the concentration-response curves
J
(bs, 1H, NH-DHP), 6.92 (s, 1H, H2-imidazole), 7.25 (s, approved by the ethics committee of Tehran University
10H, Phenyl). MS: m/z (%) 505 (M+, 1), 470 (50), 400 of Medical Sciences.
(12), 358 (12), 356 (40), 296 (5), 282 (15), 234 (37), 196
(20), 104 (100), 90 (55), 76 (25), 56 (10). Anal. Calcd.
for C28H28ClN3O4: C, 66.46; H, 5.58; N, 8.30. Found: C,
66.60; H, 5.71; N, 8.53.
Statistical analysis
The results have been presented as mean ± S.E.M.,
and the statistical significance between the groups
was analyzed by means of variance followed by one-
Diphenpropyl 4-(4(5)-chloro-1H-imidazol-5(4)-yl)- way ANOVA test.
2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxyl- dered significant.
ate (5l)
P values less than 0.05 were consi-
Using the general procedure and phenpropyl 3-oxobu-
tanoate (4l) provided the title compound after 24 h of
reflux. The solvent was removed under reduced pres-
sure and the residue was crystalized from diethyl
RESULTS
Molecular modeling and docking
The conformational study of compound 5a was done
ether to give the title compound as a white crystals, by COSMIC molecular mechanics calculations and two
yield 15%; mp 138-140oC. IR (KBr):
3400 (NH), favored tatumers were found for this compound. They
1.7-2.18 (m, 4H, were labeled as A when the imidazole substituent at
H2CH2Ph), 2.33 (s, 6H, C2, C6-CH3), 2.63 (t, = 7.91 C-4 lied in a 5-chloro tautomeric form and B when the
= 6.28 Hz, 4H,OCH2), 5.14 imidazole substituent lied in a 4-chloro tautomeric
ν
1
1
1690 (CO) cm− . H-NMR (CDCl3):
C
δ
J
Hz, 4H, CH2Ph), 4.11 (t,
J
(s, 1H, H4-DHP), 6.8 (bs, 1H, NH-DHP), 7.19 (s, 11H, form (Fig. 1). In both cases, the DHP ring showed a
H2-imidazole and Phenyl). MS: m/z (%) 533 (M+, 2), twisted boat conformation and the imidazole ring
498 (50), 370 (20), 117 (25), 91 (100), 65 (17). Anal. Calcd. occupied an axial position perpendicularly bisecting
for C30H32ClN3O4: C, 67.47; H, 6.04; N, 7.87. Found: C, the boat-like DHP ring. In addition, the ab initio cal-
67.60; H, 5.88; N, 7.99.
culation at 298 K gave 1.54 Kcal/mol for the intercon-
version of tautomers B and A. Therefore, the two pos-
sible tautomers were converted into each other at
Pharmacology
Male albino guinea-pigs (300-450 g) were sacrificed room temperature.
by a blow to the head. The intestine was removed
Docking calculations were performed using Auto-
above the ileocecal junction and longitudinal smooth dock software (vertion 4). L-type calcium channel that
muscle segments 2 cm in length were mounted under was generated by resorting to multi-body molecular

1424
M. Iman et al.
Table I. Calcium channel antagonist activity and docking
results of new DHPs 5a-l
Binding pIC50 pIC50
DHP’s
R
|REP%|d
energya Exp.b Calc.c
5a
5b
5c
5d
5e
5f
5g
5h
CH3
CH2CH3
CH2CH2CH3
CH(CH3)2
CH2CH(CH3)CH3
C(CH3)3
Cyclopentyl
Cyclohexyl
Cyclohexylmethyl
Benzyl −
Phenethyl
Phenpropyl
−
−
−
−
−
−
−
−
4.11 15.90 6.23
4.35 16.77 6.68
4.77 18.37 7.47
5.42 18.46 8.70
5.43 18.79 8.72
5.51 18.32 8.87
5.65 18.69 9.13
5.71 19.04 9.24
5.77 19.11 9.36
5.89 19.04 9.58
5.93 10.40 9.66
5.98 10.50 9.75
5.95 10.41 9.67
0.07
0.06
0.02
0.03
0.01
0.02
0.01
0.03
0.01
0.01
0.02
0.01
0.02
5i
5j
5k
−
Fig. 1. Cosmic optimized geometric for lowest energy tau-
tomeric forms in a gas phase (
and in aqueous solution ( : 5-chloro and
compound 5a
A
: 5-chloro and
B
: 4-chloro)
C
D: 4-chloro) for
−
−
−
.
5l
Nifedipine
aThe predicted binding energy (Kcal/mol).
dynamics simulations, was downloaded from the PDB
bank server (PDB entry 1T0J). In order to assign the
perfect grid of each ligand, grid box values were ob-
tained by trial and error and from our previous study
(Davood et al., 2009, 2010). Finally, docking was per-
formed using the implemented Lamarckin GL, and
the default parameters and ten independent docking
runs were performed for each DHP. Flexible docking
of all data sets used for the computational study was
carried out on the active site of L type calcium chan-
nel. The predicted binding energies of these inhibitors
into the active site have been listed in Table I.
The orientation of the most potent calcium channel
blocker, compound 5l, in the active site of L-type
calcium channel was examined through a docking
experiment (Fig. 2) (Huey and Morris, 2007). This
study indicated that in compound 5l, the oxygen of
ester (O10) and the N3' of imidazole ring formed a
hydrogen bonding interaction with the NH of HIS 363
(distance = 2.197) and the NH of LYS354 (distance =
2.008), respectively.
bThe pIC50 in guinea pig ileal smooth muscle by KCl (80
mM) was determined graphically from the dose- response
curve. There were six experiments for each compounds.
cThe pIC50 using multi linear regression Eq. (1).
dThe absolute value of the percent of the relative error of
prediction.
QSAR Model
In this study, many descriptors were calculated for
all the compounds. To select the set of descriptors that
were most relevant to the IC50 of 1,4-DHP, multi linear
regression (MLR) models were built and the QSAR
equations with stepwise selection and elimination of
variables was established using the MLR method. The
Fig. 2. Docked structures of compound 5l in the Model of
LCC. DHPs have been displayed as sticks, and hydrogen
bonds (HIS 363, LYS 354) were represented with dashed
lines (Docking study was performed by using ADT program
and LCC model obtained from PDB server).

Synthesis and Molecular Modeling of New Dihydropyridines
1425
Table II. Correlation coefficient matrix for the descriptors
of DHPs used in the MLR equation
from the dose-response curve. There were six experi-
ments for all compounds.
Correlations
DISCUSSION
BEHp5 RDF075p pIc50
Pearson Correlation
Sig. (2-tailed)
N
1
.638
.026
12
.925
.000
12
Based on our molecular modeling studies that re-
vealed 4-chloro tautomeric form was the primary form
and that it had good compatibility with nifedipine, 4-
H was syn-perpendicular, and that in the 5-chloro tau-
tomeric form, 4-H was anti-perpendicular, docking
studies were done on the 4-chloro tautomeric form. In
the docking sudies, we confirmed that the oxygen of
the ester (O10) and the N3' of the imidazole ring were
involved in forming a hydrogen bonding interaction
with the receptor. However, due to the limitations of
the scoring functions, it was often difficult to establish
a quantitative correlation between the calculated and
the experimentally derived activity values. However,
these observations and experimental results have
provided a good process for explanation of the potent
and selective inhibitory activity of these compounds.
Based on the QSAR studies (Eq. (1)), the sum of the
BEHp5 and RDF075p were identified as the most sig-
nificant descriptors. The BEHp5 belongs to the BCUT
Topological (2D) descriptors. The BCUT descriptor is a
symmetrical matrix representing molecular properties
and bonding information in its diagonal and off-diag-
onal. The RDF075p belongs to the RDF (radical distri-
bution function) descriptors that represent the atomic
polarizabilities of substituents.
BEHp5
RDF075p
pIc50
12
Pearson Correlation .638
Sig. (2-tailed)
N
1
.559
.059
12
.026
12
12
Pearson Correlation .925
Sig. (2-tailed)
N
.559
.059
12
1
.000
12
12
Fig. 3. Plot of cross-validated calculated activity obtained by
QSAR equation for new DHP derivatives.
Descriptors that belonged to the class of radial dis-
tribution function descriptors were based on the dis-
tance distribution in the geometrical representation of
correlation coefficient matrix for the descriptors used the molecule. In addition to interatomic distances in
in MLR equation has been provided in Table II.
the entire molecule, the RDF also provided valuable
information about bond distances, ring types, planar
and non-planar systems, atom types, and other impor-
(1) tant structural motifs. By using different weighting
schemes, which included atom types, electronegativ-
ity, atom mass or van der Waals radii, RDF could be
adjusted to select among those atoms of the molecule,
which gave rise to an important descriptor in deriving
Eq. SYM pIC50 = 20.397 BEHp5 – 0.062 RDF075p
– 56.659
n = 12, F = 103.59, R2 = 0.95, S = 0.18, q2 = 0.99,
p
< 0.0001.
The calculated pIC50 using MLR of Eq. (1) are present an appropriate QSAR.
in Table I and the graphical representation of cross-
The results of the pharmacologycal evaluation (Table
validated calculated activity and the experimental I) revealed that the test compounds showed a signifi-
values using equation1 have been provided in Fig. 3.
cant calcium channel antagonist activity in compari-
son to the reference drug nifedipine. The results indi-
cated that increasing the length of the chain in C3
Calcium channel antagonist evaluation
All of compounds 5a-l were evaluated as calcium and C5 ester substituents increased activity (5c > 5b >
channel antagonists using the high K+ contraction 5a). When increasing of the length or lipophilicity was
guinea-pig ileal longitudinal smooth muscle (Table I). accompanied with increasing the hindrance, the ac-
The pIC50 (pIC50 Exp) in guinea pig ileal smooth tivity decreased (5e >5f). Our results demontrated
muscle by KCl (80 mM) was determined graphically that aromatic compounds (5j-l) were more active than

1426
M. Iman et al.
Fleckenstein, A., Specific pharmacology of calcium in myo-
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was bis-phenylpropyl ester derivative (5l), which was
more active than the reference drug nifedipine, while
the bis-phenylethyl ester derivative (5k) had compar-
able activity with nifedipin.
Our pharmacological evalution revealed that all of
designed compounds were active and the present study
demonstrated that 4(5)-chloro-5(4)-imidazolyl moiety
is a bioisoster of o-nitrophenyl in nifedipine.
ACKNOWLEDGEMENTS
Goldmann, S. and Stoltefuss, J., 1,4-Dihydropyridines: effects
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This research was supported by grants (78059) from
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of Medical Sciences, TWAS-IC (The Academy of Sci-
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