Imidazo[1,2-a]pyridines linked with thiazoles/thiophene motif through keto spacer as potential cytotoxic agents and NF-κB inhibitors

• Published in: Bioorganic & medicinal chemistry letters Vol. 27; no. 24; pp. 5463 - 5466
• Main Authors: Vasu, Kamala K., Digwal, Chander Singh, Pandya, Amit N., Pandya, Dhaivat H., Sharma, Jayesh A., Patel, Sneha, Agarwal, Milee
• Format: Journal Article
• Language: English
• Published: OXFORD Elsevier Ltd 15.12.2017; Elsevier
• Subjects: A549 Cells; Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Apoptosis - drug effects; Cell Line, Tumor; Chemistry; Chemistry, Medicinal; Chemistry, Organic; Cytotoxicity; Drug Screening Assays, Antitumor; HeLa Cells; Humans; Imidazo[1,2-a]pyridine; Life Sciences & Biomedicine; NF-kappa B - antagonists & inhibitors; NF-kappa B - metabolism; NF-κB inhibitors; Pharmacology & Pharmacy; Physical Sciences; Pyridines - chemical synthesis; Pyridines - chemistry; Pyridines - pharmacology; Science & Technology; Structure-Activity Relationship; Thiazole; Thiazoles - chemistry; Thiophene; Thiophenes - chemistry; Cytotoxicity; NF-κB inhibitors; Thiophene; Thiazole; Imidazo[1,2-a]pyridine; CELLS; ACTIVATION; DESIGN; TRANSCRIPTION; ACID N-(SUBSTITUTED)PHENYLAMIDE DERIVATIVES; CANCER; KRAS MUTATIONS; THERAPY; ANTIINFLAMMATORY AGENTS; BIOLOGICAL EVALUATION; NF-kappa B inhibitors
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2017.10.060

[Display omitted] A series of new imidazo[1,2-a]pyridine linked with thiazole/thiophene motif through a keto spacer were synthesized and tested for their cytotoxic potential against three human cancer cell lines including A549, HeLa and U87-MG using MTT assay. Compounds A2, A3, A4, C1 and C2 showed cytotoxicity against all the three cell lines. The selectivity index for compound A4 for A549 and HeLa cells was comparable to that of doxorubicin. Among the synthesized compounds, B5 showed the maximum inhibition of NF-κB activity as ascertained by NF-κB reporter assay (IC50 = 6.5 ± 0.6 µM). Treatment of NCI-H23 cells (EGFR overexpressed, KRAS G12V mutant) with erlotinib and gefitinib along with compounds A4 and B5 indicated synergistic and additive potential of combination therapy.