Abstract In this work, the structural, topological and vibrational properties of an isothiazole derivatives series with antiviral activities in gas and aqueous solution phases were studied by using DFT calculations. The self consistent reaction field (SCRF) method was combined with the polarized continuum (PCM) model in order to study the solvent effects and to predict their reactivities and behaviours in both media. Thus, the 3-mercapto-5-phenyl-4-isothiazolecarbonitrile (I), 3-methylthio-5-phenyl-4-isothiazolecarbonitrile (II), 3-Ethylthio-5-phenyl-4-isothiazolecarbonitrile (III), S-[3-(4-cyano-5-phenyl)isothiazolyl] ethyl thiocarbonate (IV), 5-Phenyl-3-(4-cyano-5-phenylisothiazol-3-yl) disulphanyl-4-isothiazolecarbonitrile (V) and 1,2-Bis(4-cyano-5-phenylisothiazol-3-yl) sulphanyl Ethane (VI) derivatives were studied by using the hybrid B3LYP/6-31G* method. All the properties were compared and analyzed in function of the different R groups linked to the thiazole ring. This study clearly shows that the high polarity of (I) probably explains its elevated antiviral activity due to their facility to traverse biological membranes more rapidly than the other ones while in the (IV) and (V) derivatives the previous hydrolysis of both bonds increasing their antiviral properties inside the cell probably are related to their low S-R bond order values. In addition, the complete vibrational assignments and force constants are presented.