Synthesis and Biological Evaluation of Imidazo[2,1‐b][1,3,4]thiadiazole‐Linked Oxindoles as Potent Tubulin Polymerization Inhibitors |
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Authors: | Dr Ahmed Kamal M P Narasimha Rao Pompi Das P Swapna Sowjanya Polepalli Vijaykumar D Nimbarte Kishore Mullagiri Jeshma Kovvuri Dr Nishant Jain |
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Affiliation: | 1. Medicinal Chemistry and Pharmacology, CSIR – Indian Institute of Chemical Technology, Hyderabad 500 007 (India);2. Department of Medicinal Chemistry, National Institute of Pharmaceutical Education and Research (NIPER), Hyderabad 500 037 (India);3. Chemical Biology, CSIR – Indian Institute of Chemical Technology, Hyderabad 500 007 (India) |
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Abstract: | A series of imidazo2,1‐b]1,3,4]thiadiazole‐linked oxindoles composed of an A, B, C and D ring system were synthesized and investigated for anti‐proliferative activity in various human cancer cell lines; test compounds were variously substituted at rings C and D. Among them, compounds 7 ((E)‐5‐fluoro‐3‐((6‐p‐tolyl‐2‐(3,4,5‐trimethoxyphenyl)‐imidazo2,1‐b]1,3,4]thiadiazol‐5‐yl)methylene)indolin‐2‐one), 11 ((E)‐3‐((6‐p‐tolyl‐2‐(3,4,5‐trimethoxyphenyl)imidazo2,1‐b]1,3,4]thiadiazol‐5‐yl)methylene)indolin‐2‐one), and 15 ((E)‐6‐chloro‐3‐((6‐phenyl‐2‐(3,4,5‐trimethoxyphenyl)imidazo2,1‐b]1,3,4]thiadiazol‐5‐yl)methylene)indolin‐2‐one) exhibited potent anti‐proliferative activity. Treatment with these three compounds resulted in accumulation of cells in G2/M phase, inhibition of tubulin assembly, and increased cyclin‐B1 protein levels. Compound 7 displayed potent cytotoxicity, with an IC50 range of 1.1–1.6 μM , and inhibited tubulin polymerization with an IC50 value (0.15 μM ) lower than that of combretastatin A‐4 (1.16 μM ). Docking studies reveal that compounds 7 and 11 bind with αAsn101, βThr179, and βCys241 in the colchicine binding site of tubulin. |
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Keywords: | antitumor agents docking imidazothiadiazole‐linked oxindoles tubulin |
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