Synthesis and in-vitro anti-proliferative evaluation of some pyrazolo[1,5-a]pyrimidines as novel larotrectinib analogs.

Abstract

A series of 2-phenyl-7-(aryl)pyrazolo[1,5-a]pyrimidine-3-carbonitriles 11a-j and 2-phenyl-7-(aryl)pyrazolo[1,5-a]pyrimidine-3,6-dicarbonitriles 16a-c was synthesized by the reaction of 5-amino-3-phenyl-1H-pyrazole-4-carbonitrile (5) with 3-(dimethylamino)-1-arylprop-2-en-1-ones 6a-j or 2-aryl-3-(dimethylamino)acrylonitriles 12a-c, respectively. In addition, 7-amino-5-oxo-2-phenyl-4,5-dihydropyrazolo[1,5-a]pyrimidine-3-carbonitrile (22) was prepared from the reaction of compound 5 with ethyl cyanoacetate. The anticancer activity of the newly synthesized compounds against Huh-7, HeLa, MCF-7 and MDA-MB231 cell lines showed moderate activity of compound 11f as anti-proliferative agent against Huh-7 cell line with IC50=6.3µM when compared with doxorubicin (IC50=3.2µM). On the other hand, compound 16b revealed potent anti-proliferative activity against HeLa cell line with IC50=7.8µM when compared with doxorubicin (IC50=8.1µM). Also compound 11i exhibited a promising anti-proliferative activity against MCF-7 cell line (IC50=3.0µM) whereas IC50 of doxorubicin=5.9µM, finally compounds 11i and 16b have potent activity as anti-proliferative agents against MDA-MB231 cell line with IC50=4.32 and 5.74µM, respectively when compared with doxorubicin (IC50=6.0µM).