A series of dialkyl, dicycloalkyl, and diaryl ester analogues of nifedipine, in which the ortho-nitro phenyl group at position 4 is replaced by the 4-(5)-chloro-2-ethyl-5-(4)-imidazolyl substituent, were synthesized and evaluated as calcium channel antagonists using the high K+ contraction of guinea pig ileal longitudinal smooth muscle. The results for the symmetrical ester series showed that increasing the length of the chain in C3- and C5-ester substituents increased the activity and the most active compound was the diphenylethyl ester derivative, so it was more active than the reference drug nifedipine. In unsymmetrical diester series, when R1 is methyl or ethyl, increasing lipophilic properties in the R substituent, increased the activity. The most active compounds were methyl/phenethyl and ethyl/phenethyl ester derivatives, being slightly more active than nifedipine.
Abstract:Fifteen compounds related to ameltolide with sodium channel inhibitory activity were subjected to a molecular docking study. The chemical structures of all compounds were built using the program HyperChem and conformational studies were performed with a semiempirical method followed by the PM3 method. A docking study was performed using the program AutoDock on all the compounds. To confirm the binding mode of inhibitors, molecular dynamics simulations were performed using GROMACS 4.5.5, based upon the docked conformation of ameltolide. The docking analyses indicated that these compounds interacted mainly with residues II-S6 and III-S6 of NaV1.2 by making hydrogen bonds and ( π − π) interactions with domains I, III, and IV in the channel's inner pore. Our docking study reveals that amide linker plays a major role in the drug-receptor interaction. The results of molecular dynamic simulations confirmed the binding mode of ligands, the accuracy of docking, and the reliability of active conformations obtained by AutoDock.
1,4-Dihydropyridine has been recognized as calcium channel blocker agents. In this research we did computational studies of some newly synthesized dihydropyridine containing 4-[4-(5)-chloro-2-ethyl-5-(4)-imidazolyl] moiety. DHPs were built by the HYPERCHEM program and conformational studies were performed through semi-empirical method followed by PM3 method. QSAR descriptors were obtained from E-DRAGON. QSAR equations were obtained from multilinear regression method. This simple equation can be used to estimate the CCBs activity for new compounds of this series of compounds. The sum of the energy of the highest occupied molecular orbital (HOMO), molecular volume (MV), the GETAWAY, and the WHIM were identified as the most significant descriptors. Docking study was performed by using AutoDock4 program on the all compounds which have already been reported by Davood et al. The obtained results show that experimental PIC50 agree with docking results for potent compounds (10a, 6b). These computational studies can offer some useful references for understanding the action mechanism and performing the molecular design or modification of this series of CCB agents.
b-Phenylethylidenehydrazine (PEH) derivatives have been recognized as Gamma-aminobutyric acid aminotransferase (GABA-AT) inhibitors. In this research a group of newly synthesized of PEH analogs, possessing a variety of substituents (Me, OMe, Cl, and CF 3 ) at the 2-, 3-, and 4-position of the phenyl ring, were subjected to docking study and quantitative structure activity relationship (QSAR) analysis. PEH analogs were built by HYPERCHEM program, and conformational studies were performed through semi-empirical method followed by PM3 method. QSAR descriptors were obtained from the EDRAGON and HYPERCHEM, and equations were derived from multilinear regression (MLR) method. The sums of the JGI2, H6m, and E2s were identified as the most significant descriptors. This simple equation can be used to estimate the GABA-AT inhibitory activity for new derivatives of this series of compounds. Docking study was performed by using AutoDock4 program on the all compounds. The obtained results show that the phenyl ring is inserted into the lipophilic pocket and that the NHNH 2 moiety is situated in a mainly polar region of the enzyme. These computational studies can offer some useful references for understanding the action mechanism and performing the molecular design or modification of this series of GABA-AT inhibitors.
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