Copper(II)-catalysed one-pot synthesis of thiazole/benzothiazole-based isoquinolin-1(2H)-ones as potential cytotoxic and VEGFR-2 inhibitors

A facile one-pot annulation method for the synthesis of diverse bioactive thiazole/benzothiazole-based isoquinolin-1(2H)-one frameworks was accomplished. This approach involves the Ullman-type coupling of halo-substituted phenyl thiazolamides with various alkyl cyanoacetates employing copper (II) chloride as sustainable catalyst and water as co-solvent. Further, in silico studies were revealed the compound's selectivity towards kinase inhibition. Eventually, these derivatives were evaluated for their in vitro cytotoxicity against various Cancer cell lines such as MCF-7, HCT-116, A549, HEPG-2, and HEK-293 (normal cell line). Among them, compound 3h has displayed significant cytotoxicity with an IC₅₀ value of 7.75 ± 0.37 μM on HCT-116 cell line. Next, the compound 3h has also ability to induce Apoptosis, which is examined through various staining assays like AO/EtBr, JC-1, and ROS. An ADP Glo kinase kit is utilised to evaluate the kinase inhibitory activity with most potent compound 3h, and showed an IC₅₀ value of 1.94 μM, which is comparable to that of the standard drug sunitinib (IC₅₀ of 400 nM). Finally, this straightforward one-pot annulation protocol is amenable in the generation of a library of new thiazole/benzothiazole-based heterocyclic compounds as potential cytotoxic and VEGFR-2 inhibitors in Cancer drug discovery.

Benzothiazole; Cytotoxicity; Isoquinolin-1(2H)-one; Thiazole; Ullmann coupling; VEGFR-2 inhibition.