Novel amide and sulphonamide derivatives of 6-(piperazin-1-yl)phenanthridine as potent Mycobacterium tuberculosis H37Rv inhibitors

•33 novel phenanthridine derivatives were synthesized and evaluated for anti-TB activity.•9 analogues (MIC ≤ 3.13) exhibited excellent anti-TB activity against MTB H37RV.•In vitro toxicity studies were accomplished for most active compounds.•6b and 7d compounds were further substantiated by single crystal X-ray studies.•Compounds 6b and 7d were docked to ATPase domain of MTB GyrB protein.

A series of thirty three novel 6-(piperazin-1-yl)phenanthridine amide and sulphonamide analogues were synthesized, characterized and screened for their in vitro antimycobacterial activity against Mycobacterium tuberculosis (MTB) H37Rv strain. These compounds exhibited minimum inhibitory concentration (MIC) between 1.56 and ≥50 μg/mL. Out of these derivatives, few compounds 6l, 6r, 7b, 7f, 7g and 7k exhibited moderate activity (MIC = 6.25 μg/mL) and compounds 6b, 6e, 6k, 6n, 7h, 7i and 7n displayed good activity (MIC = 3.13 μg/mL), whereas compounds 6m, 6s and 7d exhibited excellent anti-tubercular activity (MIC = 1.56 μg/mL). In addition, MTT assay was accomplished on the active analogues of the series against mouse macrophage (RAW 264.7) cells to evaluate the toxicity profile of the newly synthesized compounds and selectivity index of the compounds was determined. Additionally, compounds 6b and 7d were docked to the ATPase domain of M. tuberculosis GyrB protein to know the interaction profile and structures of compounds 6b and 7d were further substantiated through single crystal XRD.

Graphical abstract33 Novel compounds are synthesized and evaluated for their anti-TB activity. Amongst these, 3 compounds exhibited excellent anti-TB activity with MIC 1.56 μg/mL and SI for these compounds was >46.Figure optionsDownload full-size imageDownload as PowerPoint slide