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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 GH2, 4
Authors
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Authors Affiliations
  1. 1. Department of Medicinal Chemistry, Faculty of Pharmacy, Kerman University of Medical Sciences, Kerman, Iran
  2. 2. Department of Medicinal Chemistry, Faculty of Pharmacy, Isfahan University of Medical Sciences, Isfahan, Iran
  3. 3. Department of Pharmaceutical Biotechnology, Faculty of Pharmacy, Kerman University of Medical Sciences, Kerman, Iran
  4. 4. Institute of Chemistry, Academia Sinica, Nankang, Taipei, Taiwan

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
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