Synthesis and biological evaluation of tetracyclic fluoroquinolones as antibacterial and anticancer agents

Abstract A simple and efficient synthesis of 6-fluoro-4-oxopyrido[2,3- a ]carbazole-3-carboxylic acids ( 13a – e ) and a structurally related 6-fluoro-4-oxothieno[2′,3′:4,5]pyrrolo[3,2- h ]quinoline ( 13f ) was achieved via Stille arylation of 7-chloro-6-fluoro-8-nitro-4-oxoquinoline-3-carboxylate and a subsequent microwave-assisted phosphite-mediated Cadogan reaction. The new compounds were tested for their in vitro antimicrobial and antiproliferative activity. The ability of 13a – f to inhibit the activity of DNA gyrase and topoisomerase IV was also investigated. The thieno isostere ( 13f ) emerged as the most active antibacterial, while the 9-fluoro derivative ( 13e ) was the most potent against multidrug-resistant staphylococci. Compounds 13a , 13c – f displayed growth inhibition against MCF-7 breast tumor and A549 non-small cell lung cancer cells coupled with an absence of cytotoxicity toward normal human-derm fibroblasts (HuDe). Compound 13e was the most active anticancer against MCF-7 cells, with greater potency than ellipticine (IC 50 0.8 and 1.6 μM, respectively). The most active compounds in this series show promise as dual acting anticancer and antibacterial chemotherapeutics.