Design, synthesis and characterization of novel 1,5- and 2,5-coumarin-4-yl-methyl regioisomers of 5-pyrazol-3-yl-tetrazoles as promising anticancer and antifungal agents

Abstract

A novel series of compounds was synthesized using 3-arylsydnone 1a-b. Initially, 3-arylsydnone was converted into 1-aryl-1H-pyrazole-3-carbonitriles 2a-bvia [3+2] cycloaddition with acrylonitrile by ring transformation which once again underwent [2+3] cycloaddition with sodium azide to afford 5-(1-aryl-1H-pyrazol-3-yl)-1H-tetrazoles 3a-b.These were subjected to N-alkylation with 4-bromomethyl coumarins 4c-e to afford regioisomers viz., 2,5- and 1,5-disubstituted tetrazole derivatives 5f-k and 6f-k. Single crystal X-ray analysis of compound 6f was carried out. All the synthesized compounds were characterized using various techniques including 1H NMR, 13C NMR, FT-IR, elemental analysis, and mass spectroscopy.These previously unknown compounds were screened for their anticancer activity against HCT-116 colon cancer and non-cancerous L929 cell line at a single high dose (10−5 M) concentration assay. Among the tested compounds, 6g and 5f have exhibited excellent activity with very low IC50 valuei.e.,27.85 µg/mLand 37.86 µg/mL respectively, comparable with standard Cisplatin. In the non-cancerous L929 cell line, the tested compound 6f was proven to be less toxic, and all the tested compounds exhibited toxicity at higher concentrations comparable with standard Cisplatin. Further, the in vitro antifungal activity against Candida albicans for these compounds 5f-k and 6f-k revealed potential to moderate activities compared to the standard. Moreover, docking analysis was performed to know the exact binding mode of the newly synthesized compounds with N-myristoyltransferase (PDB ID: 1IYL) from Candida albicanswhich was selected as the antifungal targets. The drug-likeness of the compound was assessed using Molinspiration, while the toxicity profile was evaluated using Protox.