Development of 3-phenyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine derivatives as novel Mycobacterium tuberculosis pantothenate synthetase inhibitors

•A high-throughput virtual screening of in-house database.•Identified pyrazolopyridine scaffold as hit compound with good MTB PS inhibition.•Synthesized 3-phenyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine derivatives for SAR.•Compound 3 identified as most effective one with no cytotoxicity.

Forty 3-phenyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine derivatives were synthesized from piperidin-4-one by five step synthesis and evaluated for Mycobacterium tuberculosis (MTB) pantothenate synthetase (PS) inhibition study, in vitro activities against MTB, cytotoxicity against RAW 264.7 cell line. Among the compounds, 1-benzoyl-N-(4-nitrophenyl)-3-phenyl-6,7-dihydro-1H-pyrazolo[4,3-c]pyridine-5(4H)-carboxamide (6ac) was found to be the most active compound with IC50 of 21.8 ± 0.8 μM against MTB PS, inhibited MTB with MIC of 26.7 μM and it was non-cytotoxic at 50 μM.

Graphical abstractCompound 1-benzoyl-N-(4-nitrophenyl)-3-phenyl-6,7-dihydro-1H-pyrazolo[4,3-c]pyridine-5(4H)-carboxamide (3) was found to be the most active compound with IC50 of 21.8 ± 0.8 μM against MTB PS, inhibited MTB with MIC of 26.7 μM and it was non-cytotoxic at 50 μM.Figure optionsDownload full-size imageDownload as PowerPoint slide