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Hybrid Pharmacophore Design, Molecular Docking, Synthesis, and Biological Evaluation of Novel Aldimine‐Type Schiff Base Derivatives as Tubulin Polymerization Inhibitor
Author(s) -
Ameri Alieh,
Khodarahmi Ghadamali,
Forootanfar Hamid,
Hassanzadeh Farshid,
Hakimelahi GholamHosein
Publication year - 2018
Publication title -
chemistry and biodiversity
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.427
H-Index - 70
eISSN - 1612-1880
pISSN - 1612-1872
DOI - 10.1002/cbdv.201700518
Subject(s) - chemistry , nitro , stereochemistry , schiff base , pharmacophore , docking (animal) , protein data bank (rcsb pdb) , aldimine , triazole , active site , tubulin , autodock , microtubule , enzyme , organic chemistry , biochemistry , medicine , alkyl , nursing , catalysis , gene , in silico , biology , microbiology and biotechnology
A series of hybrid aldimine‐type Schiff base derivatives including trimethoxyphenyl ring and 1,2,4‐triazole‐3‐thiol/thione were designed as tubulin inhibitors. The molecular docking simulations on tubulin complex ( PDB : 1SA0) revealed that derivatives with nitro and/or chloro or dimethylamino substitutes (4‐nitro, 2‐nitro, 3‐nitro, 4‐Cl‐3‐nitro, and 4‐Me 2 N) on the aldehyde ring were the best compounds with remarkable binding energies (−9.09, −9.07, −8.63, −8.11, and −8.07 kcal mol −1 , respectively) compared to colchicine (−8.12 kcal mol −1 ). These compounds were also showed remarkable binding energies from −10.66 to −9.79 and −10.12 to −8.95 kcal mol −1 on human ( PDB : 1PD8) and Candida albicans ( PDB : 3QLS) DHFR , respectively. The obtained results of cytotoxic activities against HT 1080, HepG2, HT 29, MCF ‐7, and A549 cancer cell lines indicated that 4‐nitro and 2‐nitro substituted compounds were the most effective agents by mean IC 50 values of 11.84 ± 1.01 and 19.92 ± 1.36 μ m , respectively. 4‐Nitro substituted compound (5 μ m ) and 2‐nitro substituted compound (30 μ m ) were able to strongly inhibit the tubulin polymerization compared to colchicine (5 μ m ) and 4‐nitro substituted compound displayed IC 50 values of 0.16 ± 0.01 μ m compared to that of colchicine (0.19 ± 0.01 μ m ). This compound also showed the lowest MIC values on all tested microbial strains including three Gram ‐positive, four Gram ‐negative, and three yeast pathogens.