| Title: |
Scaffold Simplification Yields Potent Antibacterial Agents That Target Bacterial Topoisomerases |
| 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 |
| Source: |
Molecules ; Volume 31 ; Issue 2 ; Pages: 240 |
| Publisher Information: |
Multidisciplinary Digital Publishing Institute |
| Publication Year: |
2026 |
| Collection: |
MDPI Open Access Publishing |
| Subject Terms: |
antibacterial agents; scaffold simplification; amino biphenyls; amino diphenyl ethers; ESKAPE pathogens; DNA replication inhibitors; topoisomerase I; DNA gyrase |
| Subject Geographic: |
agris |
| Description: |
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. |
| Document Type: |
text |
| File Description: |
application/pdf |
| Language: |
English |
| Relation: |
Medicinal Chemistry; https://dx.doi.org/10.3390/molecules31020240 |
| DOI: |
10.3390/molecules31020240 |
| Availability: |
https://doi.org/10.3390/molecules31020240 |
| Rights: |
https://creativecommons.org/licenses/by/4.0/ |
| Accession Number: |
edsbas.8E5D764A |
| Database: |
BASE |