Synthesis and biological evaluation of imidazo[2,1-b][1,3,4]thiadiazole-linked oxindoles as potent tubulin polymerization inhibitors.
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 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.
Medicinal Chemistry and Pharmacology, CSIR - Indian Institute of Chemical Technology, Hyderabad 500 007 (India); Department of Medicinal Chemistry, National Institute of Pharmaceutical Education and Research (NIPER), Hyderabad 500 037 (India). ahmedkamal@iict.res.in.
Ahmed
A
Kamal
M P Narasimha
MP
Rao
Pompi
P
Das
P
P
Swapna
Sowjanya
S
Polepalli
Vijaykumar D
VD
Nimbarte
Kishore
K
Mullagiri
Jeshma
J
Kovvuri
Nishant
N
Jain
D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology / Q000633:toxicity; D001665:Binding Sites; D045744:Cell Line, Tumor; D003078:Colchicine / Q000737:chemistry; D004354:Drug Screening Assays, Antitumor; D059565:G2 Phase Cell Cycle Checkpoints / Q000187:drug effects; D006801:Humans; D007093:Imidazoles / Q000737:chemistry*; D007211:Indoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D059566:M Phase Cell Cycle Checkpoints / Q000187:drug effects; D062105:Molecular Docking Simulation; D000078183:Oxindoles; D017434:Protein Structure, Tertiary; D013830:Thiadiazoles / Q000737:chemistry*; D014404:Tubulin / Q000737:chemistry* / Q000378:metabolism; D050257:Tubulin Modulators / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology
D000970:Antineoplastic Agents; D007093:Imidazoles; D007211:Indoles; D000078183:Oxindoles; D013830:Thiadiazoles; D014404:Tubulin; D050257:Tubulin Modulators; C586276:imidazo(2,1-b)(1,3,4)thiadiazole; C022960:2-oxindole; D003078:Colchicine
antitumor agents; docking; imidazothiadiazole-linked oxindoles; tubulin