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

Article abstract of DOI:10.1002/cbdv.201700518

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.

Full text of DOI:10.1002/cbdv.201700518

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doi: 10.1002/cbdv.201700518
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