Seeking potent anti-tubercular agents: design and synthesis of substituted-N-(6-(4-(pyrazine-2-carbonyl)piperazine/homopiperazine-1-yl)pyridin-3-yl)benzamide derivatives as anti-tubercular agents. Issue 21 (25th March 2020)

• Record Type: Journal Article
• Authors: Srinivasarao, Singireddi; Nandikolla, Adinarayana; Suresh, Amaroju; Calster, Kevin Van; De Voogt, Linda; Cappoen, Davie; Ghosh, Balaram; Aggarwal, Himanshu; Murugesan, Sankaranarayanan; Chandra Sekhar, Kondapalli Venkata Gowri
• Is Part Of: RSC advances. Volume 10:Issue 21(2020)
• Page Start: 12272
• Page End: 12288
• Publication Date: 2020-03-25
• Subjects: Chemistry -- Periodicals; 540.5
• DOI: 10.1039/d0ra01348j
• Languages: English
• ISSNs: 2046-2069

Abstract

Abstract : We herein report 27 pyrazinamide analogues as anti-tubercular agents, of which six exhibited excellent activity with IC50 ≤ 2.18 μM and these were less toxic against HEK 293 cells. Abstract : Pyrazinamide is an important first-line drug used in shortening TB therapy. In our current work, a series of novel substituted- N -(6-(4-(pyrazine-2-carbonyl)piperazine/homopiperazine-1-yl)pyridin-3-yl)benzamide derivatives were designed, synthesized, and evaluated for their anti-tubercular activity against Mycobacterium tuberculosis H37Ra. Among the tested compounds, five compounds (6a, 6e, 6h, 6j and 6k ) from Series-I and one compound (7e ) from Series-II exhibited significant activity against Mycobacterium tuberculosis H37Ra with 50% inhibitory concentrations (IC50 ) ranging from 1.35 to 2.18 μM. To evaluate the efficacy of these compounds, we examined their IC90 values. Five of the most active compounds were found to be more active with IC90 s ranging from 3.73 to 4.00 μM and one compound (6e ) showed an IC90 of 40.32 μM. Moreover, single crystals were developed for 6d, 6f and 6n . In addition, most active compounds were evaluated for their cytotoxicity on HEK-293 (human embryonic kidney) cells. Our results indicate that the compounds are nontoxic to human cells. The molecular interactions of the derivatised conjugates in docking studies reveal their suitability for further development.