Novel pyrazine based anti-tubercular agents: Design, synthesis, biological evaluation and in silico studies.

Bioorganic Chemistry
Nayera W HassanSoad A M El-Hawash

Abstract

TB continues to be a leading health threat despite the availability of powerful anti-TB drugs. We report herein the design and synthesis of various hybrid molecules comprising pyrazine scaffold and various formerly identified anti-mycobacterial moieties. Thirty-one compounds were screened in vitro for their activity against Mycobacterium tuberculosis H37Rv strain using MABA assay. The results revealed that six compounds (8a, 8b, 8c, 8d, 14b and 18) displayed significant activity against Mtb with MIC values ≤6.25 µg/ml versus 6.25 µg/ml for pyrazinamide. The most active compounds were then assessed for their in vitro cytotoxicity against PBMC normal cell line using MTT assay and showed SI > 200. Several in silico studies have been carried out for target fishing of the novel compounds such as shape-based similarity, pharmacophore mapping and inverse docking. Based on this multi-step target fishing study, we suggest that pantothenate synthetase could be the possible target responsible for the action of these compounds. The most active compounds were then successfully docked into the active site of pantothenate synthetase enzyme with favorable binding interactions. In addition, in silico prediction of physicochemical, ADMET and dru...Continue Reading

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Related Concepts

Metazoa
Antitubercular Agents
In Silico
Canis familiaris
Homo sapiens
Breakpoint Determination, Antibacterial Susceptibility
Models, Molecular
Mycobacterium tuberculosis H37Rv
Pyrazines
Structure-Activity Relationship

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