Design, synthesis of DNA-interactive 4-thiazolidinone-based indolo-/pyrroloazepinone conjugates as potential cytotoxic and topoisomerase I inhibitors

• Published in: European journal of medicinal chemistry 2022-08, Vol.238, p.114465-114465, Article 114465
• Main Authors: Kadagathur, Manasa, Patra, Sandip, Devabattula, Geetanjali, George, Joel, Phanindranath, Regur, Shaikh, Arbaz Sujat, Sigalapalli, Dilep Kumar, Godugu, Chandraiah, Nagesh, Narayana, Tangellamudi, Neelima D., Shankaraiah, Nagula
• Format: Article
• Language: English
• Subjects: Anticancer; DNA intercalation; Indoloazepinone; Molecular modeling; Pyrroloazepinone; Thiazolidinone; Topoisomerase I inhibition
• ISSN: 0223-5234; 1768-3254
• DOI: 10.1016/j.ejmech.2022.114465

With the rising cancer incidence and mortality globally, there is a prerequisite for effective design strategies towards the discovery of newer small molecular entities in chemotherapy. Hence, a series of new thiazolidinone-based indolo-/pyrroloazepinone conjugates was designed, synthesized via molecular hybridization, and evaluated for their in vitro cytotoxicity potential and DNA topoisomerase I and II inhibition. Among this series, conjugate 11g emerged as the most active compound with an IC50 value of 1.24 μM against A549 and 3.02–10.91 μM in the other tested cancer cell lines. Gratifyingly, 11g displayed 43-fold higher selectivity towards A549 cancer cells as compared to the non-cancer cells. Subsequently, conjugate 12g also demonstrated significant cytotoxicity against SK-MEL-28 cells. Basing the in vitro cytotoxicity results, SAR was established. Later, the conjugates 11g and 12g were further evaluated for their apoptosis-inducing ability, which was quantified by flow cytometric analysis, DNA-binding, Topo I inhibitory activity and IC50 value calculation. Molecular modeling studies provided profound insights about the binding nature of these compounds with DNA-Topo I complex. In silico ADME/T and prediction studies corroborated the drug-likeness of the two investigated compounds. TOPKAT toxicity profiling studies demonstrated the compounds’ safety in many animal models with a minimal toxicological profile. Encouraging results obtained from in vitro and in silico studies could put this series of conjugates at the forefront of cancer drug discovery. [Display omitted] •26 conjugates were synthesized and evaluated against human cancer cell lines.•11g (indoloazepinone) and 12g (pyrroloazepinone) showed potent in vitro against A549 and SK-MEL-28 cells, respectively.•Apoptosis-inducing capability, DNA-binding and Topo I inhibitory activity of 11g and 12g were evaluated.•Insilico molecular modeling studies espoused the in vitro results.