Anti-pharmacophore Identification and Structure-Activity Relationships for the Inhibition of Cellular Protein and DNA Synthesis by a Series of Thiosemicarbazones and Thiosemicarbazides

Background: Structure-activity relationship (SAR) of a series of thiosemicarbazone and thiosemicarbazide derivatives (57 compounds) that are potent inhibitors of herpes simplex virus (HSV) has been investigated for their inhibitory effects on cellular protein and DNA syntheses by electron-conformational method. SAR and QSAR studies were already carried out for these compounds in terms of their anti-HSV activity and dermal toxicity. The effect of a compound on cellular growth needs also to be known before its usage in chemotherapy. Therefore, this is a complementary study in designing new nontoxic antiviral drugs with reduced side effects on protein and DNA syntheses. Methods: Electron-conformational method, which considers both electronic and geometrical structures of compounds, was applied. Computed geometrical and electron structural parameters of each atom and bond were arranged as a matrix for each of the 57 compounds. A submatrix that is common (absent) in the inhibitory (noninhibitory) compounds within some certain tolerances was searched to obtain the anti-pharmacophore responsible for the inhibition of cellular protein and DNA syntheses. A multivariable regression analysis was carried out to obtain a classical QSAR equation that relates the inhibitory concentrations with some physicochemical characteristics of the compounds. Results: The molecular fragment associated to the revealed submatrix is formed by three charges situated at some specific distances. It is considered responsible for the inhibition of cellular protein and DNA syntheses (anti-pharmacophore). The realization of the identified anti-pharmacophore has been discussed on several compounds. The found QSAR equation has been validated on a test series and shown that it can be used in predicting the extent of the inhibitory effect of the untested compounds. Conclusion: This study allows one to design new anti-herpes simplex virus agents with reduced side effects on protein and DNA syntheses.