Synthesis and anti-mitotic activity of 6,7-dihydro-4H-isothiazolo[4,5-b]pyridin-5-ones: In vivo and cell-based studies.

A series of 3,7-diaryl-6,7-dihydroisothiazolo [4,5-b]pyridin-5(4H)-ones 8 and 9 was synthesized by multicomponent condensation of 3-aryl-5-isothiazolecarboxylic acid esters 4a-f with aromatic (or thienyl) aldehydes 7 and Meldrum's acid in an acidic medium. The targeted compounds were evaluated for their antimitotic microtubule destabilizing activity using in vivo phenotypic sea urchin embryo model and in vitro human cancer cell-based assays. Selected dihydroisothiazolopyridinones altered sea urchin egg cleavage in 2-10 nM concentrations together with significant cytotoxicity against cancer cells including chemoresistant cell lines (IC in submicromolar - low nanomolar concentration range). Both approaches confirmed antimitotic microtubule destabilizing mechanism of action of the izothiazole derivatives. Structure-activity relationship study determined the importance of p-methoxybenzene A-ring for the antiproliferative effect. The most potent compound 9b containing p-methoxybenzene A-ring and thiophene B-ring caused mitotic arrest and disintegration of cell microtubules.