Chromatography-Free Synthesis of β-Carboline 1‑Hydrazides and an Investigation of the Mechanism of Their Bioactivity: The Discovery of β-Carbolines as Promising Antifungal and Antibacterial Candidates

• Published in: Journal of medicinal chemistry 2023-07, Vol.66 (13), p.9040-9056
• Main Authors: Sheng, Tao, Yu, Chenjie, Wang, Yujie, Li, Shengkun, Wu, Huijun, Gu, Qin, Meng, Guangrong, Herron, Alastair N., Gao, Xuewen
• Format: Article
• Language: English
• Subjects: Anti-Bacterial Agents - pharmacology; Antifungal Agents - pharmacology; Carbolines - chemistry; Structure-Activity Relationship
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/acs.jmedchem.3c00650

Agrochemical science prioritizes the discovery and effective synthesis of innovative and promising lead compounds. Herein, we developed an efficient column chromatography-free synthesis for β-carboline 1-hydrazides via a mild CuBr2-catalyzed oxidation and investigated the antifungal and antibacterial activities and mechanisms for these compounds. In our study, compounds 4de (EC50 = 0.23 μg·mL–1) and 4dq (EC50 = 0.11 μg·mL–1) displayed the best efficacy, demonstrating enhancements in inhibitory activity of more than 20-fold against Ggt compared to silthiopham (EC50 = 2.39 μg·mL–1). Additionally, compound 4de (EC50 = 0.21 μg·mL–1) demonstrated outstanding in vitro antifungal activities as well as in vivo curative activities against Fg. According to preliminary mechanistic studies, β-carboline 1-hydrazides led to the accumulation of reactive oxygen species, destruction of cell membranes, and dysregulation of histone acetylation. Furthermore, several substances exhibited antibacterial activity against Psg and Cms by preventing the development of bacterial biofilms.