Pyrazoline-based mycobactin analogues as MAO-inhibitors

3,5-Diaryl carbothioamide pyrazolines designed as mycobactin analogs (mycobacterial siderophore) were reported to be potent antitubercular agents under iron limiting condition in our earlier study. Clinical complications of newly introduced antibiotic Linezolid, due its MAO inhibitory activity, prompted us to evaluate our compounds for their MAO-inhibitory activity against rat liver MAO-A and MAO-B as pyrazolines were reported to be antidepressants and MAO inhibitors. The present study carried out with this pilot library of 32 compounds will provide us with necessary information for designing antitubercular molecules with reduced MAO-inhibitory activity and also help us in identifying a selective MAO-B inhibitor which has potential clinical utility in neurodegenerative disorders. Thirty-two compounds analyzed has shown spectrum of activity from selective to nonselective against two isoforms of rat liver MAO-A and MAO-B and also as competitive, reversible to non-competitive, irreversible. It is also interesting to note that anti-tubercular compound 11, 14 and 16 were also found to be selective inhibitors of rat liver MAO-B. Docking studies with human MAO shows that compound 11 interacts with the catalytic site of both the isoforms, suggesting compound 11 as nonselective inhibitor of human MAO isoforms.

Thirty-two member pilot library of pyrazolines, synthesized as mycobactin analogues, were tested for MAO-inhibitory activity. Compound 7 (IC50: 2.84 ± 0.19 μM) and 11 (IC50: 19.45 ± 1.02 μM) were found to be potent and selective inhibitors of rat liver MAO-A and MAO-B, respectively. Docking studies revealed compound 11 as nonselective inhibitor of human MAO-A and MAO-B and others as selective towards human MAO-A.Figure optionsDownload as PowerPoint slide