Multicomponent synthesis, <i>in vitro</i> cytotoxic evaluation and <i>molecular modelling</i> studies of polyfunctionalized pyrazolo[3,4-<i>b</i>]pyridine derivatives against three human cancer cell lines
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A series of diversely polyfunctionalized pyrazolo[3,4-<i>b</i>]pyridines were synthesized by the multicomponent reaction of phenyl/benzothiazolylhydrazine and 3-oxo-3-arylpropanenitrile with 1,3-diketones under solvent-free and solvent-mediated conditions. Nineteen pyrazolo[3,4-<i>b</i>]pyridine derivatives were screened for their anti-cancer activity against three human cancer cell lines namely NALM-6, SB-ALL and MCF-7. Non-fluorinated 1-(benzothiazolyl)pyrazolo[3,4-<i>b</i>]pyridines (<b>6a</b>–<b>d</b>) displayed better cytotoxicity results as compared to other tested derivatives. The compound 1-(benzothiazolyl)-4,6-dimethyl-3-(4-chlorophenyl)pyrazolo[3,4-<i>b</i>]pyridine, <b>6b</b>, was identified as the most active derivative with 53% cell growth inhibition nearly equal to the standard drug doxorubicin (58%), in close agreement to drug-likeness and drug score predictions. Among the fluorinated derivatives, compound 2-(3-(4-chlorophenyl)-4-methyl-6-(trifluoromethyl)-1<i>H</i>-pyrazolo[3,4-<i>b</i>]pyridin-1-yl)benzo[<i>d</i>]thiazole, <b>12c</b>, was identified as hit compound with 46-39% cell growth inhibition against all the tested cell lines. Compound <b>6b</b> was found to display suitable binding when docked inside the active site of Aurora-A kinase enzyme.
