Purine analogs: synthesis, evaluation and molecular dynamics of pyrazolopyrimidines based benzothiazole as anticancer...

Cyclin dependent kinases (CDKs) enzymes regulate cell proliferation and transcriptional processes and can be considered as important targets for the development of anticancer and antimicrobial drugs. In this work, novel benzothiazolyl pyrazolopyrimidine carboxamide and benzothiazolyl pyrazolopyrimidine carbonitrile derivatives were synthesized and characterized. The synthetic process was carried out via the reaction of ylidine benzothiazole derivatives with pyrazolocarboxamide and pyrazolocarbonitrile through a Michael addition pathway. Docking studies were done against CDK2 and CDK9 enzymes and revealed that compound 8a showed high free energy of binding against CDK2 (-8.10 kcal/mol) while compound 15a showed the highest free energy of binding against CDK2 (-8.16 kcal/mol) and CDK9 (-7.87 kcal/mol). Molecular dynamics simulations were conducted to compare the stability of binding of the most active compound 15a and the potent reference drugs roscovitine and dinaciclib. A CDK enzyme assay was done against CDK2 and CDK9 for the previously mentioned top-ranked compounds, 8a and 15a. It was found that compound 15a was the most potent inhibitor for both enzymes with IC₅₀ of 127 ± 1.01 nM and 65 ± 0.50 nM. The anticancer activity of the synthesized compounds was also determined by NCI against 60 cell lines. Compound 8a showed the highest cytotoxic activity against a large number of the tested cell lines. The antimicrobial activity of the synthesized compounds was determined against various gram positive and gram-negative bacteria as well as fungi. The results showed that compound 15a had the strongest antibacterial activity.