Quantitative structure-activity relationship studies help chemist to find chemical facts about the mechanism of action and/or behavior of the system under study. In this study, quantitative structure-activity relationship was employed as a promising tool to investigate some chemical, electronic, and structural features affecting on the antileishmanial activity of 5-substituted-1,3,4-thiadiazole derivatives. A data set, consisting of 21 thiadiazole derivatives with known in vitro leishmanicidal activity, was taken and semi-empirical AM1 quantum chemical calculation was employed to find the optimum three-dimensional geometry of the molecules. Multiple linear regression-based quantitative structure-activity relationship models were obtained between the antileishmanial activity and electronic, chemical, and topological descriptors of the molecules. Model performances and predictivity were evaluated using leave-one-out cross-validation method. The resulted models had good prediction ability (0.83 > q(2) > 0.71) and thus they described the structure-activity relationships in a useful manner. It was obtained that LUMO molecular orbital energy represents significant impact on the leishmanicidal activity. This means that the molecules may act on the leishmania parasites through an electron transfer reaction. Further theoretical investigations suggested that one probable mechanism for the activity of the thiadiazole derivatives may be due to the reduction of -NO(2) substituents of the molecules to -NO.

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