Synthesis and Biological Evaluation of Imadazo[1,2-<i>a</i>]pyrazines as Anticancer and Antiviral Agents through Inhibition of CDK9 and Human Coronavirus

• Main Authors: Aisha A. Alsfouk (Author), Hanan M. Alshibl (Author), Bshra A. Alsfouk (Author), Najla A. Altwaijry (Author), Ebtehal S. Al-Abdullah (Author)
• Format: Book
• Published: MDPI AG, 2022-07-01T00:00:00Z.
• Subjects: article
• Online Access: Connect to this object online.

Summary

In this work, novel imadazo[1,2-<i>a</i>]pyrazine derivatives were synthesized and evaluated as CDK9 inhibitors. The results of CDK9 assay showed that the derivatives with pyridin-4-yl in position 2 and benzyl in position 3 of imadazo[1,2-<i>a</i>]pyrazine <b>3c</b> displayed the most potent CDK9 inhibitory activity with IC₅₀ of 0.16 µM. The anti-proliferative effect of the new compounds was examined against breast cancer (MCF7), colorectal cancer (HCT116), and chronic myelogenous leukaemia (K652) cell lines. The data of MTT assay showed that the cytotoxic effect of the inhibitors is correlated to their inhibitory activity against CDK9. Compound <b>3c</b> exhibited the most potent cytotoxicity effect with average IC₅₀s of three cell lines of 6.66 µM. The drug likeness properties of <b>3c</b> were predicated in silico and demonstrated that <b>3c</b> have reasonable physiochemical and pharmacokinetic properties. Selected derivatives were assessed in antiviral assay against human coronavirus 229E. The results of this assay showed that the derivative with pyridin-4-yl in position 2 and cyclohexyl in position 3 of imadazo[1,2-<i>a</i>]pyrazine <b>3b</b> exhibited the most potent anti-coronaviral activity with IC₅₀ of 56.96 µM and selectivity index of 7.14. The target predication result revealed that <b>3b</b> showed high affinity to protease enzyme. Docking studies of <b>3b</b> with COVID-19 main protease was conducted and showed good binding affinity, which confirmed the in vitro assay data.

Item Description

10.3390/ph15070859
1424-8247