Design and synthesis of unique indole-benzosulfonamide oleanolic acid derivatives as potent antibacterial agents against MRSA

• Published in: European journal of medicinal chemistry 2024-10, Vol.276, p.116625, Article 116625
• Main Authors: Li, Jinxuan, Sun, Ying, Su, Kaize, Wang, Xu, Deng, Duanyu, Li, Xiaofang, Liang, Lihua, Huang, Wenhuan, Shang, Xiangcun, Wang, Yan, Zhang, Zhen, Ang, Song, Wong, Wing-Leung, Wu, Panpan, Hong, Weiqian David
• Format: Article
• Language: English
• Subjects: Animals; Anti-Bacterial Agents - chemical synthesis; Anti-Bacterial Agents - chemistry; Anti-Bacterial Agents - pharmacology; Anti-MRSA; Biofilms - drug effects; Dose-Response Relationship, Drug; Drug Design; HEK293 Cells; Humans; Indole-benzosulfonamide; Indoles - chemical synthesis; Indoles - chemistry; Indoles - pharmacology; Methicillin-Resistant Staphylococcus aureus - drug effects; Mice; Microbial Sensitivity Tests; Molecular Structure; NIH 3T3 Cells; Oleanolic Acid - chemical synthesis; Oleanolic Acid - chemistry; Oleanolic Acid - pharmacology; Oleanolic acid derivatives; Staphylococcal Infections - drug therapy; Structure-Activity Relationship; Sulfonamides - chemical synthesis; Sulfonamides - chemistry; Sulfonamides - pharmacology; Synthesis
• ISSN: 0223-5234; 1768-3254; 1768-3254
• DOI: 10.1016/j.ejmech.2024.116625

The rapid emergence of antibiotic resistance and the scarcity of novel antibacterial agents have necessitated an urgent pursuit for the discovery and development of novel antibacterial agents against multidrug-resistant bacteria. This study involved the design and synthesis of series of novel indole-benzosulfonamide oleanolic acid (OA) derivatives, in which the indole and benzosulfonamide pharmacophores were introduced into the OA skeleton semisynthetically. These target OA derivatives show antibacterial activity against Staphylococcus strains in vitro and in vivo. Among them, derivative c17 was the most promising antibacterial agent while compared with the positive control of norfloxacin, especially against methicillin-resistant Staphylococcus aureus (MRSA) in vitro. In addition, derivative c17 also showed remarkable efficacy against MRSA-infected murine skin model, leading to a significant reduction of bacterial counts during this in vivo study. Furthermore, some preliminary studies indicated that derivative c17 could effectively inhibit and eradicate the biofilm formation, disrupt the integrity of the bacterial cell membrane. Moreover, derivative c17 showed low hemolytic activity and low toxicity to mammalian cells of NIH 3T3 and HEK 293T. These aforementioned findings strongly support the potential of novel indole-benzosulfonamide OA derivatives as anti-MRSA agents. [Display omitted] •Novel indole-benzosulfonamide oleanolic acid derivatives were constructed.•Derivative c17 showed more potential than norfloxacin against MRSA.•Derivative c17 could disrupt cell membrane and restrain metabolism.•Derivative c17 showed antibacterial efficacy in MRSA-infected skin murine model.