Discovery of pyran annulated heterocyclic scaffolds linked to carboxamide fragments: Anticancer evaluation, topoisomerase I/II, tyrosine kinase receptor inhibition and molecular docking studies

A class of 4H-benzo[h]chromene (4a-h) and 1H-benzo[f]chromene (6a-h) derivatives linked to carboxamide/ carbothioamide at the 3/2-positions were designed and synthesized with the intent of cultivating efficacious antitumor agents. The pursued benzochromenes were successfully authenticated via the employment of an array of spectral assays. Subsequently, an antiproliferative evaluation against a selected line of tumorous cells (MCF-7, HepG-2, and PC-3) were performed in-vitro for the novel benzochromenes (4a-h and 6a-g) with the superior cytotoxically-active molecules subjected to additional assessment against the non-cancerogenic cells (HFL-1 and WI-38). Compounds 4a, 6b, 6c, 6d, 6f, and 6g demonstrated high efficiency towards MCF-7, HepG-2, and PC-3 cell lines, analogous to that of Vinblastine, Doxorubicin, and feeble efficacy against normal cell lines. The inhibition activity of the selected molecules (4a, 6b, 6c, 6d, 6f, and 6g) was detected in the G2/M phase of the cell cycle, which similarly instigated the suppression of the topoisomerase I & II enzymes in order to yield this result. Additionally, the derivatives submitted for the topoisomerase inhibition appraisal were similarly subjugated to examinations regarding the inhibition of tyrosine kinase receptors EGFR and VEGFR-2, in which the results were successively contrasted against the reference kinase inhibitor Sorafenib. Lastly, the molecular docking assay of the highly potent and efficacious derivatives in correlation with the active enzymatic and kinase sites was addressed.