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

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 m, respectively. 4-Nitro substituted compound (5 m) and 2-nitro substituted compound (30 m) were able to strongly inhibit the tubulin polymerization compared to colchicine (5 m) and 4-nitro substituted compound displayed IC50 values of 0.16 +/- 0.01 m compared to that of colchicine (0.19 +/- 0.01 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.