Multicomponent synthesis, in vitro cytotoxic evaluation and molecular modelling studies of polyfunctionalized pyrazolo[3,4-b]pyridine derivatives against three human cancer cell lines

Abstract

A series of diversely polyfunctionalized pyrazolo[3,4-b]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-b]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-b]pyridines (6a–d) displayed better cytotoxicity results as compared to other tested derivatives. The compound 1-(benzothiazolyl)-4,6-dimethyl-3-(4-chlorophenyl)pyrazolo[3,4-b]pyridine, 6b, 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)-1H-pyrazolo[3,4-b]pyridin-1-yl)benzo[d]thiazole, 12c, was identified as hit compound with 46-39% cell growth inhibition against all the tested cell lines. Compound 6b was found to display suitable binding when docked inside the active site of Aurora-A kinase enzyme.

Graphical Abstract

Keywords:

• Cytotoxicity
• in silico studies
• multi-component synthesis
• Pyrazolo[3,4-b]pyridines
• solvent-free

Acknowledgments

Authors are thankful to UGC, New Delhi, India for providing financial assistance in the form of Rajiv Gandhi National, Senior Research Fellowship to Suresh Kumar. Thanks are due to Central Instrumentation Laboratory, Guru Jambheshwar University, Hisar, India for providing spectral facilty. Rachna Sadana would like to thank the University of Houston-Downtown for providing her organized research and creative activities (ORCA) funds.

Authors’ contributions

Prof. Ranjana Aggarwal contributed to the overall designing of the work and the preparation of the manuscript. Suresh Kumar has synthesized all the new compounds and has contributed to the write-up. Rachna and Andrea Ghuzman have performed the biological evaluation of all the compounds. Virender Kumar has contributed to synthesizing compounds.

Disclosure statement

The authors declare no conflict of interest.

Additional information

Funding

This study was supported by UGC, New Delhi, India, [Grant No. RGNF-2012-2013-SC-HAR-15378].