ABSTRACT
We recently described the synthesis and antiviral activity of the compounds 5-phenyl-3-(4-cyano-5-phenylisothiazol-3-yl) disulphanyl-4-isothiazolecarbonitrile and S-(4-cyano-5-phenylisothiazol -3-yl)-O-ethyl thiocarbonate, which were found to be effective against both HIV-1 (IIIB) and HIV-2 (ROD). We have now evaluated these compounds against both RNA and DNA viruses, obtaining high selectivity indexes for poliovirus 1 (SI: 223 and 828, respectively) and Echovirus 9 (SI: 334 and 200, respectively). In our previous studies, 3-methylthio-5-(4-OBn-phenyl)-4-isothiazolecarbonitrile was found to exhibit a broad spectrum of action against picornaviruses, we therefore selected this compound and S-(4-cyano-5-phenylisothiazol-3-yl)-O-ethyl thiocarbonate as the model for the synthesis of a new isothiazole derivative, S-[4-cyano-5-(4-OBn-phenyl)isothiazol-3-yl]-O-ethyl thiocarbonate. This compound was evaluated against picornaviruses, measles virus, HIV-1 (IIIB) and HIV-2 (ROD), and some DNA viruses (adenovirus type 2 and herpes simplex virus type 1). The compound was shown to be active against rhinoviruses 2, 39, 86 and 89, Coxsackie B1 and measles virus.
Subject(s)
Antiviral Agents/pharmacology , Disulfides/pharmacology , Thiazoles/pharmacology , Viruses/drug effects , Animals , Antiviral Agents/chemical synthesis , Antiviral Agents/chemistry , Cell Line , Cell Survival/drug effects , Chlorocebus aethiops , Disulfides/chemical synthesis , Disulfides/chemistry , Humans , Mice , Microbial Sensitivity Tests , Molecular Structure , Structure-Activity Relationship , Thiazoles/chemical synthesis , Thiazoles/chemistryABSTRACT
A series of 3,4,5-trisubstituted isothiazoles has been screened against HIV-1 (IIIB) 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 (IIIB) and HIV-2 (ROD) at 50% effective concentrations (EC50) of 7.8 and 9.7 microg/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 (IIIB) (EC50=13.6 and 15.2 microg/ml, respectively) and HIV-2 (ROD) (EC50=17.4 and 13.4 microg/ml, respectively).