Premium
Synthesis and Biological Evaluation of Imidazo[2,1‐ b ][1,3,4]thiadiazole‐Linked Oxindoles as Potent Tubulin Polymerization Inhibitors
Author(s) -
Kamal Ahmed,
Rao M. P. Narasimha,
Das Pompi,
Swapna P.,
Polepalli Sowjanya,
Nimbarte Vijaykumar D.,
Mullagiri Kishore,
Kovvuri Jeshma,
Jain Nishant
Publication year - 2014
Publication title -
chemmedchem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.817
H-Index - 100
eISSN - 1860-7187
pISSN - 1860-7179
DOI - 10.1002/cmdc.201400069
Subject(s) - chemistry , tubulin , stereochemistry , combretastatin , cytotoxicity , methylene , docking (animal) , microtubule , in vitro , biochemistry , medicinal chemistry , biology , medicine , nursing , microbiology and biotechnology
A series of imidazo[2,1‐ 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)‐imidazo[2,1‐ b ][1,3,4]thiadiazol‐5‐yl)methylene)indolin‐2‐one), 11 (( E )‐3‐((6‐ p ‐tolyl‐2‐(3,4,5‐trimethoxyphenyl)imidazo[2,1‐ b ][1,3,4]thiadiazol‐5‐yl)methylene)indolin‐2‐one), and 15 (( E )‐6‐chloro‐3‐((6‐phenyl‐2‐(3,4,5‐trimethoxyphenyl)imidazo[2,1‐ 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 G 2 /M phase, inhibition of tubulin assembly, and increased cyclin‐B1 protein levels. Compound 7 displayed potent cytotoxicity, with an IC 50 range of 1.1–1.6 μ M , and inhibited tubulin polymerization with an IC 50 value (0.15 μ M ) lower than that of combretastatin A‐4 (1.16 μ M ). Docking studies reveal that compounds 7 and 11 bind with αAsn101, βThr179, and βCys241 in the colchicine binding site of tubulin.