THIENYLIMIDAZO[2,1-B]THIAZOLES AS INHIBITORS OF MITOCHONDRIAL NADH DEHYDROGENASE

The synthesis of B-substituted 5-(thienylvinyl)imidazo[2,1-b]thiazoles and 6-thienylimidazo-[2,1-b]thiazoles is reported. These compounds we re tested as specific inhibitors of the NADH: ubiquinone (UBQ) reducta se activity of NADH dehydrogenase in mitochondrial membranes. The 6-th ienylimidazo[2,1-b]thiazoles were more potent in mammalian than in nem atode mitochondria and had an average titer of 0.11 mM for 2-methyl-6- (2-thienyl)imidazo[2,1-b]-thiazole (10). This compound is noncompetiti ve with the ubiquinone substrate and interacts with a site which is mu tually exclusive with that of rotenone but nonexclusive with that of p iericidin and several other inhibitors of NADH dehydrogenase. In the s eries of 5-(thienylvinyl)-imidazothiazoles, the hydrobromide of -6-chl oro-5-(2-thienylvinyl)imidazo[2,1-b]thiazole (E-5.HBr) was found to be more patent as an inhibitor of the NADH:UBQ and activity (IC50 = 15-1 7 mu M) than the 6-thienylimidazoles such as 10. The inhibitory action of E-5.HBr and its analogs is different from that of compound 10 as i ndicated by the mutual exclusivity with other inhibitors and the relat ive inhibition of the activity with various electron accepters.