Design synthesis and biological activity of novel heterocyclic compounds as anti tubercular agents

Abstract

Mycobacterium tuberculosis, the fatal agent of humans is estimated to claim two million deaths annually. Even though the existing drugs possess huge value in controlling disease to some extent, there are still several shortcomings. The drug discovery efforts are progressively becoming more rational, focusing at various enzymes and identification of appropriate targets become fundamental pre-requisite. In the present study we paid attention on achieving promising anti-tubercular agents by design, synthesis and anti-mycobacterial evaluation of compounds based on reported promising anti-tubercular agents. In the present work, four series of compounds (total 232 compounds) were designed and synthesized by conventional methods. Wherever possible, reactions were carried out using environmental benign techniques such as microwave assisted organic synthesis or under solvent free conditions with moderate to excellent yields. All synthesized novel compounds were characterized by various spectroscopic techniques (IR, NMR and MS), elemental analysis and structures of few compounds are confirmed by single crystal X-ray Diffraction (XRD). All synthesized compounds were screened for antimycobacterial activity against Mycobacterium tuberculosis H37Rv strain and furthermore, most active compounds were evaluated for their in vitro cytotoxicity against RAW 264.7 cell line (mouse leukemic monocyte macrophage) using MTT assay. Amongst, 232, twenty one compounds were found to be more active in inhibiting MTB H37Rv compared to standard anti-TB drugs viz. ethambutol and pyrazinamide, whereas one compound possessed better MTB MIC than ciprofloxacin. Over all the synthesized compounds, BIP 53, BIP 58, BIP 63, BIP 65, QNP 17, QNP 19, QNP 22, QNP 32, QNP 45, QNP 48, QNP 53, PPA 18, PPA 24, PPA 28, IPO 17, IPO 21, IPO 25, IPO 29, IPO 37 and IPO 57 (MTB MIC = 1.56 and#956;g/mL SI and#8805; 34) emerged as the most promising anti-tubercular drug candidates. Compound QNP 27 emerged as the most potent compound with MTB MIC = 0.78 and#956;g/mL and SI gt 135. The present