Ameri Alieh, Khodarahmi Ghadamali, Forootanfar Hamid, Hassanzadeh Farshid, Hakimelahi Gholam-Hosein
Department of Medicinal Chemistry, Faculty of Pharmacy, Kerman University of Medical Sciences, Kerman, Iran.
Department of Medicinal Chemistry, Faculty of Pharmacy, Isfahan University of Medical Sciences, Isfahan, Iran.
Chem Biodivers. 2018 Mar;15(3):e1700518. doi: 10.1002/cbdv.201700518. Epub 2018 Mar 7.
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 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 , respectively) compared to colchicine (-8.12 kcal mol ). These compounds were also showed remarkable binding energies from -10.66 to -9.79 and -10.12 to -8.95 kcal mol 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 IC 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 IC 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.
设计了一系列包含三甲氧基苯基环和1,2,4-三唑-3-硫醇/硫酮的杂化醛亚胺型席夫碱衍生物作为微管蛋白抑制剂。对微管蛋白复合物（PDB：1SA0）进行的分子对接模拟表明，醛环上带有硝基和/或氯或二甲基氨基取代基（4-硝基、2-硝基、3-硝基、4-氯-3-硝基和4-甲基氨基）的衍生物是最佳化合物，与秋水仙碱（-8.12 kcal/mol）相比，具有显著的结合能（分别为-9.09、-9.07、-8.63、-8.11和-8.07 kcal/mol）。这些化合物在人源（PDB：1PD8）和白色念珠菌（PDB：3QLS）二氢叶酸还原酶上也分别显示出显著的结合能，范围为-10.66至-9.79 kcal/mol和-10.12至-8.95 kcal/mol。针对HT1080、HepG2、HT29、MCF-7和A549癌细胞系的细胞毒性活性测试结果表明，4-硝基和2-硝基取代的化合物是最有效的药物，平均IC值分别为11.84±1.01和19.92±1.36μm。与秋水仙碱（5μm）相比，4-硝基取代的化合物（5μm）和2-硝基取代的化合物（30μm）能够强烈抑制微管蛋白聚合，并且4-硝基取代的化合物的IC值为0.16±0.01μm，而秋水仙碱的IC值为0.19±0.01μm。该化合物在所有测试的微生物菌株上也显示出最低的MIC值，包括三种革兰氏阳性菌、四种革兰氏阴性菌和三种酵母病原体。
