Synthesis, anticancer evaluation, and molecular modeling study of new 2-(phenylamino)pyrazolo [1,5-a]pyrimidine analogues

The reaction of 3-amino-5-phenylaminopyrazoles 2 with 3-(dimethylamino) acrylonitrile derivatives resulted in a series of substituted pyrazolopyrimidine analogues 4 and 6. The DFT stud-ies of the isolated compounds showed that the frontier molecular orbitals energy gap was close and in the 2.65-2.81 eV range where the derivative 6b has the lowest and both of 4a and 4c have the highest values. Meanwhile, the anticancer activity of the newly synthesized pyrazolopyrimidine ana-logues have been tested against several different cell lines (MCF-7, PC3, Hep-2 and WI38). The investigated pyrazolopyrimidines showed remarkable cytotoxicity activity against the MCF-7 and Hep-2 cell lines. In comparison to the effects of 5-fluorouracil, IC50 = 10.19 +/- 0.42 and 7.19 +/- 0.47, compounds 6a-c demonstrated potential anticancer activity with IC50 values for MCF-7 (10.80 +/- 0.36-19.84 +/- 0.49 lM) and Hep-2 (8.85 +/- 0.24-12.76 +/- 0.16 lM). Important details regarding the protein's binding sites were disclosed when the produced analogues docked with the crystal structure of the KDM5A protein, which was located in the protein data library.(c) 2022 The Author(s). Published by Elsevier B.V. on behalf of King Saud University. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).