Molecules, Vol. 31, Pages 240: Scaffold Simplification Yields Potent Antibacterial Agents That Target Bacterial Topoisomerases

Molecules doi: 10.3390/molecules31020240

Authors:
Lyubov Khudiakova
Kristina Komarova
Maxim Zhuravlev
Dmitry Deniskin
Alexey Golovanov
Artemiy Nichugovskiy
Kirill Babkin
Maria Zakharova
Mikhail Chudinov
Elizaveta Rogacheva
Lyudmila Kraeva
Olga Shevtsova
Daria Ipatova
Dmitry Skvortsov
Dmitrii Lukianov
Maxim Kryakvin
Maxim Gureev
Alexey Lukin

This work describes the lead optimization of a promising class of antibacterial compounds, derived from a previously reported N-[4-(4-fluorophenoxy)phenyl]-6-(methylsulfonyl)-2,6-diazaspiro [3.4]octane-8-carboxamide (LK1819), through systematic scaffold simplification. A novel series of amide derivatives were designed and synthesized, exploring key structural variations, including the replacement of the diphenyl ether core with a biphenyl system. All compounds were evaluated for in vitro antibacterial activity against the ESKAPE panel of pathogens. The most potent simplified analogs demonstrated exceptional, broad-spectrum activity, with minimum inhibitory concentrations (MICs) that were 10 to 100 times lower than the control antibiotic ciprofloxacin against many strains. Mechanistic studies using a reporter system and enzymatic assays revealed that the compounds do not inhibit protein synthesis but disrupt DNA replication, exhibiting a dose-dependent inhibitory effect on bacterial topoisomerase I and DNA gyrase. The compounds showed moderate toxicity against human cell lines, consistent with their DNA-targeting mechanism, but cytotoxicity assays indicated a sufficient selectivity window. We conclude that scaffold simplification successfully yielded highly potent antibacterial agents with a defined mechanism of action, presenting a promising foundation for further development as antibiotics and potentially as anticancer agents.

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Lyubov Khudiakova www.mdpi.com