Purine analogues as potential CDK9 inhibitors: New pyrazolopyrimidines as anti-avian influenza virus

Abstract

Cyclin dependent kinases (CDKs) are a group of enzymes involved in different phases of the cell cycle. In addition, it has been reported that CDK9 could be used as a crucial target for the development of antiviral drugs such as purine analogues; roscovitine and dinaciclib. A new series of benzothiazolyl pyrazolopyrimidine carboxamide derivatives were synthesized and evaluated for their antiviral activity against avian influenza "bird flu" (H5N1). The novel compounds were synthesized via the reaction of pyrazolo carboxamide derivatives with different derivatives of ylidine benzothiazole. The reaction proceeded via a Michael addition pathway. Antiviral activity was determined using a plaque reduction assay against the H5N1 virus. Five compounds showed the highest inhibitory activity in the range of 61.6 to 71.6% at 0.1 μmol/mL. Based on a molecular docking study, an enzyme assay was carried out against CDK9 for the previously mentioned top-ranked compounds. It was found that compound 11f was the most potent inhibitor of CDK9 with an IC₅₀ of 0.062 μmol/mL. A QSAR model was built to determine the hidden feature responsible for the biological activity of the novel compounds. It was found that two sets of descriptors, 3 D Potential energy descriptors and 2 D Atom Counts and Bond Counts descriptors, were correlated to a linear model with RMSE and r2 coefficient values of 0.75 and 0.80, respectively. A molecular dynamic simulations study of 11f over 10 ns against dinaciclib showed that both 11f and dinaciclib achieved equilibrium at 2 Å.

Supplemental data for this article is available online at https://doi.org/10.1080/15257770.2022.2059674 .

Keywords:

• Pyrazolo[1,5-a] pyrimidine
• chemical synthesis
• molecular dynamic simulation and QSAR
• anti-avian influenza virus
• CDK9 Inhibitors

Disclosure statement

No potential conflict of interest was reported by the authors.

Funding

The author(s) reported there is no funding associated with the work featured in this article.