Design, Synthesis, and in vitro Biological Evaluation of ROS‐Generating Phenanthridin‐trione‐Epoxide Conjugates as Agents against Mycobacterium tuberculosis

• Published in: ChemistrySelect (Weinheim) Vol. 8; no. 25
• Main Authors: Mamgain, Ritu, Swami, Sagar, Sarkar, Dhiman, Srivastava, Pratibha
• Format: Journal Article
• Language: English
• Published: 07.07.2023
• Subjects: antimycobacterial agents; Computational docking; Cystine adduct; Epoxy-Phenanthridinone-triazoles; ROS generation
• ISSN: 2365-6549; 2365-6549
• DOI: 10.1002/slct.202300416

Tuberculosis (TB) is one of the devasting infectious diseases and continues to spread among people despite having several specific drugs. Total eradication of TB is one of the shared interests of both the World Health Organization (WHO) and India globally. A library of antitubercular 6‐((1‐(aryl/heteroaryl)‐1H‐1,2,3‐triazol‐4‐yl)methyl)oxireno[2,3‐b] phenanthridine‐5,7,9(6H,7aH,8aH)‐trione (6 a–e) has been prepared in five steps including click chemistry and tested against active and dormant strains of Mycobacterium tuberculosis H37Ra using XRMA protocol. The result showed the inhibitory potential of 6 d IC50 at 0.74 μg/mL concentration against active strain and at 0.9 μg/mL against the dormant strain of Mtb. ROS generating ability of the compounds has been confirmed by luminol, H2O2, and glutathione assays. The molecular docking with the thioredoxin protein of Mtb showed a docking score of −9.6 Kcal/mol. To understand the mechanism with the thioredoxin protein of Mtb, the adduct formation of compounds with cystine was confirmed with HPLC. The involvement of lead molecules with existing drugs can be helpful in the eradication of tuberculosis. We report a systemic approach for the synthesis of phenanthridin‐trione‐epoxy conjugates as antitubercular agents. Their inhibitory potential at low concentrations toward both active and dormant strains of Mycobacterium tuberculosis makes them potential lead molecules as antitubercular agents or adjuvants.