Isolation, Functionalization, In Silico Investigation, and Synthesis of 1,8-Cineole Analog as Antitubercular Agent Targeting InhA

• Published in: Russian journal of bioorganic chemistry Vol. 49; no. 2; pp. 390 - 402
• Main Authors: Sabarees, G., Gouthaman, S., Alagarsamy, V., Velmurugan, V., Solomon, V. Raja
• Format: Journal Article
• Language: English
• Published: Moscow Pleiades Publishing 01.04.2023; Springer Nature B.V
• Subjects: Biochemistry; Biomedical and Life Sciences; Biomedicine; Bioorganic Chemistry; Drugs; Ethanol; Functional groups; Inhibitors; Life Sciences; NMR; Nuclear magnetic resonance; Optimization; Organic Chemistry; Reductases; Synthesis; Tuberculosis; biological assay; molecular docking; virtual screening; tuberculosis; inha
• ISSN: 1068-1620; 1608-330X
• DOI: 10.1134/S1068162023020206

A desirable and established target for creating antituberculosis drug lead molecules is the Mycobacterium tuberculosis enoyl-acyl carrier protein reductase InhA. Additionally, direct inhibitors of InhA continue to be effective against InhA variants with mutations linked to isoniazid resistance, providing the possibility of activity against MDR isolates. Initially, we isolated monoterpenoid 1,8-cineole from leaf parts of the Callistemon citrinus by aqueous ethanol extract, followed functionalization with several functional groups, and we created a novel 1,8-cineole analogue as a novel compound for treating tuberculosis infection. This study used a structure-based virtual screening of 20 structures to identify novel lead InhA inhibitors as potential antituberculosis drugs. Compound ( SG01 ) was identified as a lead candidate for the synthesis and has been characterized by IR, 1 H, 13 C NMR, and mass spectroscopy. Using a microplate Alamar Blue assay method, the compound was also tested for their in vitro antimycobacterial activity against the H37Rv strain. This compound offers a desirable starting point for ligand optimization attempts to find new and potent anti-tuberculosis drugs that target InhA.