3D QSAR studies on amphiphilic indoles for antimycobacterial activity

• Published in: Journal of biochemical and molecular toxicology Vol. 35; no. 3; pp. e22675 - n/a
• Main Authors: Bahuguna, Aparna, Bharatam, Prasad V., Rawat, Diwan S.
• Format: Journal Article
• Language: English
• Published: United States Wiley Subscription Services, Inc 01.03.2021
• Subjects: 3D‐QSAR; amphiphilic indoles; Antibiotics; Antimycobacterial agents; Bactericidal activity; Cell membranes; Hydrogen bonds; Indoles; Mycobacterium bovis BCG; Mycobacterium tuberculosis; Root-mean-square errors; Structure-activity relationships; Three dimensional models; 3D-QSAR; amphiphilic indoles; Mycobacterium tuberculosis; Mycobacterium bovis BCG; antimycobacterial agents
• ISSN: 1095-6670; 1099-0461
• DOI: 10.1002/jbt.22675

A persistent infection prolongs treatment duration and also enhances the chance of resistance development against antibiotics. Recently, a class of amphiphilic indole derivatives was discovered exhibiting bactericidal activity against both growing and nongrowing Mycobacterium bovis BCG (M. bovis BCG). These antibacterials are suggested to disturb the integrity and functioning of the cell membrane, a property that can help eradicate persistent organisms. This study article describes field‐based three‐dimensional quantitative structure–activity relationship (3D‐QSAR) studies of 79 amphiphilic indole derivatives. The aim of this QSAR study is to optimize this class of compounds for the development of more potent antimycobacterial agents. The results obtained indicate that steric interactions are crucial for antimycobacterial activity, while hydrogen bond donor groups participate negligibly in activity. The derived 3D‐QSAR models showed acceptable r2 (0.91) and q2 (0.91) with a root mean squared error (RMSE) of 0.08. The models were cross‐validated using the leave‐one‐out method. Applying the same QSAR model to another congeneric series of amphiphilic indoles externally validated the QSAR model. The model could appreciably predict the activity (pMIC50) of this congeneric series of amphiphilic indoles, with an RMSE of 0.49, indicating the robustness of the model and its efficiency in predicting the potentially active compounds.