Novel quinolone substituted thiazolidin-4-ones as anti-inflammatory, anticancer agents: Design, synthesis and biological screening

• Published in: European journal of medicinal chemistry 2013-05, Vol.63, p.589-602
• Main Authors: Suthar, Sharad Kumar, Jaiswal, Varun, Lohan, Sandeep, Bansal, Sumit, Chaudhary, Anil, Tiwari, Amit, Alex, Angel Treasa, Joesph, Alex
• Format: Article
• Language: English
• Subjects: Animals; Anti-inflammatory; Anti-Inflammatory Agents - chemical synthesis; Anti-Inflammatory Agents - chemistry; Anti-Inflammatory Agents - pharmacology; Anticancer; Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Apoptosis - drug effects; Carcinoma, Ehrlich Tumor - prevention & control; Carrageenan; Cell Line, Tumor; Cell Survival - drug effects; Docking; Drug Design; Drug Screening Assays, Antitumor; Edema - chemically induced; Edema - prevention & control; HeLa Cells; Humans; Inhibitory Concentration 50; Mice; Models, Chemical; Models, Molecular; Molecular Structure; NF-kappa B - chemistry; NF-kappa B - metabolism; NF-κB; Protein Binding; Protein Structure, Tertiary; Quinolone; Quinolones - chemistry; Rats; Thiazolidin-4-one; Thiazolidines - chemical synthesis; Thiazolidines - chemistry; Thiazolidines - pharmacology
• ISSN: 0223-5234; 1768-3254
• DOI: 10.1016/j.ejmech.2013.03.011

Nuclear factor-kappaB (NF-κB) has been reported to regulate various genes involved in cancer and inflammation. Accordingly, drugs suppressing or inhibiting NF-κB may possess both anti-inflammatory and anticancer properties. A library of quinolone substituted thiazolidin-4-ones was docked into the active site of NF-κB and the top-ranked 31 compounds were synthesized and evaluated for anti-inflammatory and anticancer activity. The best-ranked compound 6b showed highest anti-inflammatory activity in carrageenan-induced paw edema model. In vitro anticancer studies revealed 1a and 16a as most active compounds against BT-549, HeLa, COLO-205 and ACHN human cancer cell lines. Compounds 1a and 16a exhibited NF-κB dependent anticancer properties and apoptosis mediated cell death. In vivo Ehrlich ascites carcinoma study further confirmed the antitumor activity of 1a and 16a. [Display omitted] Compound 1a docked on MF-κB homodimer. The amino acids Gln 274, and Gln 306 involved in hydrogen bond interactions with 1a. •Quinolone substituted thiazolidin-4-ones were docked into active site of NF-κB.•Top ranked 31 quinolone substituted thiazolidin-4-ones were synthesized.•The best-ranked compound 6b showed potent in vivo anti-inflammatory activity.•Compounds 1a and 16a showed NF-κB dependent anticancer properties.•In vivo Ehrlich ascites carcinoma model confirmed antitumor activity of 1a and 16a.