Antibacterial activity of indolyl-quinolinium derivatives and study their mode of action

• Published in: Bioorganic & medicinal chemistry Vol. 27; no. 7; pp. 1274 - 1282
• Main Authors: Cai, Senyuan, Yuan, Wenchang, Li, Ying, Huang, Xuanhe, Guo, Qi, Tang, Ziwei, Fang, Zhiyuan, Lin, Hai, Wong, Wing-Leung, Wong, Kwok-Yin, Lu, Yu-Jing, Sun, Ning
• Format: Journal Article
• Language: English
• Published: OXFORD Elsevier Ltd 01.04.2019; Elsevier
• Subjects: Anti-Bacterial Agents - chemical synthesis; Anti-Bacterial Agents - chemistry; Anti-Bacterial Agents - pharmacology; Antibacterial activity; Biochemistry & Molecular Biology; Cells division; Chemistry; Chemistry, Medicinal; Chemistry, Organic; Dose-Response Relationship, Drug; Drug Resistance, Bacterial - drug effects; Drug resistant bacteria; FtsZ; Gram-Negative Bacteria - drug effects; Gram-Positive Bacteria - drug effects; Indoles - chemistry; Indoles - pharmacology; Indolyl quinolinium derivatives; Life Sciences & Biomedicine; Microbial Sensitivity Tests; Molecular Structure; Pharmacology & Pharmacy; Physical Sciences; Quinolinium Compounds - chemistry; Quinolinium Compounds - pharmacology; Science & Technology; Structure-Activity Relationship; Antibacterial activity; FtsZ; Indolyl quinolinium derivatives; Drug resistant bacteria; Cells division; CELL-DIVISION; DESIGN; ANTIBIOTICS; FTSZ INHIBITORS; AGENTS
• ISSN: 0968-0896; 1464-3391
• DOI: 10.1016/j.bmc.2019.02.024

A new series of indolyl-quinolinium derivatives perturb the polymerization of FtsZ with strong antibacterial activities. [Display omitted] •Novel indolyl-quinolinium derivatives were synthesized.•The antibacterial activity of quinolinium derivatives were evaluated.•c2 and c9 possess potent antibacterial activity against MRSA and VRE.•Biological assays suggest antibacterial activity of c2 may associated with FtsZ. Filamenting temperature-sensitive mutant Z (FtsZ) is recognized as a promising target for new antibiotics development because of its high conservatism and pivotal role in the bacteria cell division. The aromatic heterocyclic scaffold of indole is known showing merit medical functions in antiviral and antimicrobial. In the present study, a series of 1-methylquinolinium derivatives, which were integrated with an indole fragment at its 2-position and a variety of amino groups (cyclic or linear, mono- or di-amine) at the 4-position were synthesized and their antibacterial activities were evaluated. The results of antibacterial study show that the representative compounds can effectively inhibit the growth of testing strains including MRSA and VRE, with MIC values of 1–4 μg/mL by bactericidal mode. The mode of action assays revealed that c2 can effectively disrupt the rate of GTP hydrolysis and dynamic polymerization of FtsZ, and thus inhibits bacterial cell division and then causes bacterial cell death. In addition, the result of resistance generation experiment reveals that c2 is not likely to induce resistance in S. aureus.