Synthesis of 2,4-diaryl chromenopyridines and evaluation of their topoisomerase I and II inhibitory activity, cytotoxicity, and structure–activity relationship

Designed and synthesized were a series of 5H-chromeno[4,3-b]pyridines with substitution at 2- and 4-positions with various 5- or 6-membered heteroaromatics as antitumor agents. They were evaluated for topoisomerase I and II inhibitory activities as well as cytotoxicities against several human cancer cell lines. Structure–activity relationship study showed that 2-furyl or 2-thienyl at 2- or 4-position of central pyridine is crucial in displaying topo I or II inhibitory activity and cytotoxicity.

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► Twenty three conformationally constrained rigid 2,4-diaryl chromenopyridines were synthesized for topo I and II inhibitors.
► Compounds 15, 24, 27, and 28 displayed significant topo I inhibitory activity.
► Compounds 14, 15, 26, and 36 exhibited moderate topo II inhibitory activity.
►  Compounds 24, 26, and 28 exhibited strong cytotoxicity.
► 2- Furyl or 2-thienyl at 2- or 4-position of central pyridine is crucial in displaying topo I or II inhibitory activity and cytotoxicity.