Design, synthesis and evaluation of novel Se-alkylated pyrazoles and their cyclized analogs as potential anticancer agents

Abstract

A simple multicomponent reaction (MCR) was utilized to synthesize a series of 5-alkylated selanyl-1H-pyrazole derivatives 3a-d, 6a-d, and their 4-amino-5-substituted selenolo[2,3-c]pyrazole analogs (4a-d). The methodology is based on the substitution of selenium for the chlorine atom in the chloro pyrazole carbonitrile compound 1via reduction with sodium borohydride in a nitrogen atmosphere, followed by in-situ substitution reactions with various α-halo alkylating agents in the presence of a basic catalyst. The structures of the compounds were confirmed using elemental and spectroscopic techniques (FT-IR, 1H, 13C NMR, and mass spectrometry). The compounds were screened for their anticancer activity which showed promising results and compounds 4c and 6d exhibited the highest cytotoxicity against the HepG2 cell line with pIC50 values of 4.30 and 4.49 respectively, without showing any off-target toxicity. These molecules also, displayed good ADMET features, passed Lipinski's filters, showed good drug-likeness properties, and were predicted to be effective dual EGFR and VEGFR-2 inhibitors, causing downregulation of S100A4 and MMP-9 genes. Together, these results make these molecules as important lead molecules that could be studied further for their anticancer properties.