Hybrid Pharmacophore Design, Molecular Docking, Synthesis, and Biological Evaluation of Novel Aldimine-Type Schiff Base Derivatives As Tubulin Polymerization Inhibitor Publisher Pubmed



Ameri A¹ ; Khodarahmi G² ; Forootanfar H³ ; Hassanzadeh F² ; Hakimelahi GH^{2, 4}
Source: Chemistry and Biodiversity Published:2018

Abstract

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-Me2N) 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 HT1080, HepG2, HT29, MCF-7, and A549 cancer cell lines indicated that 4-nitro and 2-nitro substituted compounds were the most effective agents by mean IC50 values of 11.84 ± 1.01 and 19.92 ± 1.36 μm, respectively. 4-Nitro substituted compound (5 μm) and 2-nitro substituted compound (30 μm) were able to strongly inhibit the tubulin polymerization compared to colchicine (5 μm) and 4-nitro substituted compound displayed IC50 values of 0.16 ± 0.01 μm compared to that of colchicine (0.19 ± 0.01 μm). This compound also showed the lowest MIC values on all tested microbial strains including three Gram-positive, four Gram-negative, and three yeast pathogens. © 2018 Wiley-VHCA AG, Zurich, Switzerland