Asghar Davood

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

New analogues of nifedipine, in which the ortho-nitro phenyl group at position 4 has been replaced by 4(5)-chloro-5(4)-imidazolyl substituent and which are able to interact with the receptor by hydrogen binding were designed, synthesized, and evaluated as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.

Synthesis and docking studies of new 1,4-dihydropyridines containing 4-(5)-Chloro-2-ethyl-5-(4)-imidazolyl substituent as novel calcium channel agonist

Abstract1,4-Dihydropyridines have been recognized as calcium channel agonist. Three new analogues of Bay K8644 in which the ortho trifluromethyl phenyl group at position 4 is replaced by the 4-(5)-Chloro-2-ethyl-5-(4)-imidazolyl substituent, were designed and synthesized as calcium channel agonist. For this propose, the structures of designed compounds were drawn by HYPERCHEM program. Conformations of the compounds were optimized through semi-empirical method followed by PM3 calculation. Then the crystalin stucture of L-type calcium channel was obtained from the Protein Data Bank (PDB) server. Docking calculations were carried out using Auto-Dock.4 program. The good interaction of our 1,4-DHP derivatives showed that they can be as possible calcium channel agonist agents. Finally compounds were synthesized according to a modified Hantzsch condensation procedure.

Computational studies of new 1,4-dihydropyridines containing 4-(5)-chloro-2-ethyl-5-(4)-imidazolyl substituent: QSAR and docking

Abstract1,4-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.

QSAR and QSTR study of pyrimidine derivatives to improve their therapeutic index as antileishmanial agents

AbstractIn the treatment of leishmaniasis, chemotherapy is expensive and has various side effects. The major side effects are due to multiple injections that are required over a course of several weeks and non-selectivity of the drugs. In addition, there is no fully effective drug available against the cutaneous form of the disease. Experimental data of pyrimidine derivatives show that they are potent inhibitors of Leishmania growth. In the current study, a series of 2-pyridyl pyrimidine derivatives with Plasmodium falciparum methionine aminopeptidase 1b inhibitory activity was subjected to quantitative structure activity relationship (QSAR) and quantitative structure toxicity relationship (QSTR) analyses to identify the ideal physicochemical characteristics of potential anti Leishmania activity with limited cytotoxic effects. We also determined the physicochemical characteristics that affect antiparasitic activity and cytotoxicity to identify the best relationship model related to these two parameters. 2-Pyridyl pyrimidines with desirable properties were built using HyperChem program, and conformational studies were performed through the semi-empirical method followed by the PM3 force field. Different descriptors were calculated using Dragon and HyperChem software. Multilinear regression was used as a chemometric tool for QSAR and QSTR modeling and the developed models were shown to be statistically significant according to the validation parameters. Based on our computational studies, using lipophilic and electronegative moieties can improve the therapeutic index of pyrimidine derivatives.Graphical Abstract Quantitative structure activity relationships (QSAR) used to improve the therapeutic index of the pyrimidine derivatives as antileishmanial agents and Quantitative structure toxicity relationships (QSTR) used to improve the low cytotoxicity of the pyrimidine derivatives.

Docking and QSAR studies of β-phenylethylidenehydrazine derivatives as a Gamma-aminobutyric acid aminotransferase inhibitor

Abstractβ-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 CF3) 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 NHNH2 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.

Design, Synthesis and Protection Against Pentylenetetrazole-induced Seizure of N-aryl Derivatives of the Phthalimide Pharmacophore

A series of compounds including N-aryl substituents of phthalimide and 4-nitrophthalimide were synthesized and evaluated for their anticonvulsant properties. The in vivo screening data suggest that all the analogs have the ability to protect against pentylenetetrazole-induced seizures. These compounds exerted their maximal effects 30 min after administration. The most potent compound in both, tonic and clonic seizure was 1-naphthyl derivative (comp. 6), which was more active than the reference drug known as Phenytoin. Using an open pore model of the Na channel, these anticonvulsants were docked in the active site and examined in relation to the residues identified by mutagenesis as important for their binding energies. Docking studies revealed that all compounds (1-13) interacted mainly with residues II-S6 of NaV1.2 by making hydrogen bonds and additional hydrophobic interactions with domain I and II in the channels inner pore.

Homology modeling of lanosterol 14α-demethylase of Candida albicans and insights into azole binding

Candida albicans is one of the most common causes of invasive fungal infections. Azole antifungal agents are widely used as fungal antibiotics which inhibit the cytochrome P450 sterol 14α-demethylase (CYP51). This study describes the homology modeling and three-dimensional model of CYP51 from C. albicans SC5314. Dope score, GA341 of Modeller, PROCHECK statistics, Ramachandran, and G-factors were used to analyze and evaluate a final model. Molecular docking identified the binding mode of the azole antifungal agents with modeled CYP51. The obtained results of Autodock program, compounds 1–4, were determined the heterocyclic nitrogen atom of azole bound to the heme iron atom in the binding site of the enzyme. Based on the results of this study, we conclude that the structural model of C. albicans SC5314 can be used in azole optimization, virtual screening and de novo inhibitor design for the discovery of new antifungal agents.Graphical AbstractThis study describes the homology modeling and three-dimensional model of CYP51 from C. albicans SC5314. Dope score and GA341 of Modeller, and PROCHECK statistics, Ramachandran, and G-factors were used to analysis and evaluate of the final model.

QSAR and QSTR study of selenocyanate derivatives to improve their therapeutic index as anti- leishmanial agents

AbstractExperimental data of selenocyanate derivatives show that they are potent inhibitors of Leishmania growth. In the current study, a series of selenocyanate derivatives were subjected to quantitative structure activity relationship and quantitative structure toxicity relationship analyses to identify the ideal physicochemical characteristics of potential anti-leishmanial activity with limited cytotoxic effects. Selenocyanate were built using HyperChem program, and conformational studies were performed through the semi-empirical method followed by the PM3 force field. Multi-linear regression was used as a chemo metric tool. The developed models were shown to be statistically significant according to the validation parameters. Based on our computational studies four descriptors, SPAM, P2e, B08 [N–N] and G2p can affect the activity and the cytotoxicity of selenocyanate derivatives.Graphical AbstractQuantitative structure activity relationships were used to improve the therapeutic index and quantitative structure toxicity relationships were used to improve the low cytotoxicity of selenocyanate derivatives as anti-leishmanial agents.

Docking and QSAR studies of new 1,4-dihydropyridines containing 4(5)-chloro-2-methyl-5(4)-imidazolyl substituent

Abstract1,4-Dihydropyridine (1,4-DHP) derivatives have been recognized as calcium channel blocker (CCB) agent. In this research, a newly synthesized dihydropyridine, containing 4-[4(5)-chloro-2-methyl-5(4)-imidazolyl] moiety, as subjected to docking study and QSAR analysis. DHPs 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. QSAR equations were derived from multilinear regression method. This simple equation can be used to estimate the CCB’s activity for new derivatives of this series of compounds. The sums of the HATS2v, Mor09p, Mor06p, and CIC5 were identified as the most significant descriptors. Docking study was performed using AutoDock4 program on all of the compounds. The results show that experimental pIC50 values agree with docking results for potent compounds. These computational studies can offer useful references for understanding the action mechanism and molecular design or modification of this series of the CCB agents.

Design and Synthesis of Curcumin-Like Diarylpentanoid Analogues as Potential Anticancer Agents.

BACKGROUND Curcumin is a polyphenolic natural compound with multiple targets that used for the prophylaxis and treatment of some type of cancers like cervical and pancreatic cancers. Some recent patent for curcumin for cancer has also been reviewed. OBJECTIVE In this study, ten new curcumin derivatives were designed and synthesized and their cytostatic activity evaluated against the Hela and Panc cell lines that some of them showed more activity than curcumin. METHOD In the present study, a series of mono-carbonyl derivatives of curcumin were designed and prepared. The details of the synthesis and chemical characterization of the synthesized compounds are described. The cytostatic activities of the designed compounds are assessed in two different tumor cell lines using MTT test. RESULTS In vitro screening for human cervix carcinoma cell lines (Hela) and pancreatic cell lines (Panc-1) at 24 and 48 hour showed that all the analogs possessed good activity against these tumor cell lines and compounds 5a, 5c and 6 with high potency can be used as a new lead compounds for the designing and finding new and potent cytostatic agents. Docking studies indicated that compound 5c readily binds the active site of human glyoxalase I protein via two strong hydrogen bonds engaging residues of Glu-99 and Lys-156. CONCLUSION Our results are useful in guiding a design of optimized ligands with improved pharmacokinetic properties and increased of anti-cancer activity vs. the prototype curcumin compound.