Novel Class of Fluorinated Pyrazolo[1,5‐a]pyrimidines as CDK5 and Bcl2 Inhibitors: Design, Synthesis, Biological Evaluation, Molecular Docking and ADME Studies

Abstract

New pyrazolo[1,5‐a]pyrimidines were designed and synthesized based on the structural analysis of known CDK5 inhibitors. Biological evaluations showed that the IC50 of the most potent compounds 3 c and 5 b targeting normal WI38 (human lung cells) were 74.13±4.0 and 56.19±3.5 μM, respectively and showed safety profile in normal cells compared to doxorubicin with IC50 of 6.27±0.5 μM. Compounds 3 c and 5 b, demonstrated potent CDK5 inhibitory activity with IC50=0.36±0.02 and 0.226±0.01 μM, respectively compared to roscovitine of IC50 value 0.149±0.007 μM. Compound 5 b also cause a significantly increased the percentage of cells at phases in S by 1.2 fold, compared to untreated cells. It was found that downregulation of Bcl2 expression by 3 and 6 folds for 3 c and 5 b, respectively than that the control in breast cell. In addition, examination of the induction of apoptosis by 5 b demonstrated that compound 5 b significantly increased the early and late apoptotic ratio by about 65 and 66 folds, respectively, proving that compound 5 b significantly induces apoptotic by 34.5 %. Moreover, the pharmacokinetic properties of 3 c and 5 b were predicted using ADME calculations, which revealed that they inhibit some CYP450 enzymes in the liver.