Isothiazole Derivatives as Novel HIV Replication Inhibitors

A series of 3,4,5-trisubstituted isothiazoles has been screened against HIV-1 (III B ) and HIV-2 (ROD) at sub-toxic concentrations in acutely infected MT-4 cells. Among the tested compounds, only 3-mercapto-5-phenyl-4-isothiazolecarbonitrile was found to inhibit the replication of HIV-1 (III B ) and HIV-2 (ROD) at 50% effective concentrations (EC 50 ) of 7.8 and 9.7 μg/ml, respectively. The presence of a thioalkyl chain or dialkylamino function in the 3-position caused a loss of anti-HIV activity. New 4-cyano-5-phenylisothiazoles with other substituents in the 3-position have also been synthesized and studied as potential anti-HIV agents. Our results have demonstrated that 5-phenyl-3-(4-cyano-5-phenylisothiazol-3-yl) disulphanyl-4-isothiazolecarbonitrile and S-(4-cyano-5-phenylisothiazol-3-yl)- O-ethyl thiocarbonate are effective against both HIV-1 (III B ) (EC 50 =13.6 and 15.2 μg/ml, respectively) and HIV-2 (ROD) (EC 50 =17.4 and 13.4 μg/ml, respectively).