Antirhinovirus activity of 3-methylthio-5-aryl-4-isothiazolecarbonitrile derivatives

A series of 3-methylthio-5-aryl-4-isothiazolecarbonitriles has been evaluat ed as anti rhinovirus agents against a panel. of 17 representative human rh inovirus (HRV) serotypes, belonging to both A and B groups. No anti rhinovi rus activity was detected for 3-methylthio-5-phenyl-4-isothiazolecarbonitri le (IS-2). Isothiazole derivatives with bulky substituents (O-Bn or O-But g roups) on the para position of the phenyl ring were the most effective comp ounds of this series. In fact, a reduction in virus-induced cytopathogenici ty was demonstrated for the O-Bn substituted IS-50 compound against the maj ority (88%) of the rhinoviruses tested, whereas the compound with an O-Ts g roup (IS-44) was found to be a specific inhibitor of group B serotypes, exh ibiting the lowest IC50 against HRVs type 2, 85 and 89. Our studies on the mechanism of action of IS-44 demonstrated that it prevents the thermal inac tivation of HRV 2 infectivity, probably due to a conformational shift in th e viral capsid and a decrease in affinity for the cellular receptor, result ing in an inhibition of attachment of the virions. (C) 2000 Elsevier Scienc e B.V. All rights reserved.