Cytotoxic, Antibacterial, and in Silico Pks13 Inhibitory Properties of Indole‐Coupled Dihydrobenzo[c]phenanthridines

The benzylic indolization of dihydrosanguinarine (1) and dihydrochelerythrine (2) allows us to develop the promising antimycobacterial hit 1a, having a greater than tenfold selectivity in killing Mycobacterium tuberculosis compared to human cells (HaCaT), in addition to the promising anticancer agent 1g, having a greater than fourfold difference between cytotoxicity against HaCaT and cytotoxicity against cancer cell lines (PC-3 and MCF-7).

The indoles and benzo[c]phenanthridines have attracted much interest as potential anticancer and antibacterial agents. Herein, the synthesis and bioactivity of new and known indole-coupled dihydrobenzo[c]phenanthridines are reported. Among the investigated compounds, 2j displays potent and selective activity against drug-resistant Staphylococcus aureus, S. epidermidis, and Enterococcus faecium strains. In addition, 1a-c and 2a specifically target the multidrug-resistant Mycobacterium tuberculosis G122, possibly by inhibiting the Pks13 enzyme, as deduced from the in silico analyses. Additionally, compound 1g is more potent than cisplatin against MCF-7 (breast) and PC-3 (prostate) human cancer cell lines, whereas 2b is found to be almost as active as cisplatin against PC-3 and SW-480 (colorectal) cell lines. Compounds 1a and 1g display remarkable selectivity index values, thus being promising antibacterial and anticancer hits.

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