Molecular Highlights about Leishmanicidal Activity and Cytotoxicity of Quinoxaline Derivatives: A Combination of Ligand-based QSAR/QSTR Approaches

Background: Leishmaniasis is a neglected tropical disease, considered endemic in almost 98 countries worldwide, with 250 million new cases estimated annually. The usual drugs are considered toxic, expensive and frequently ineffective, justifying the search for new lead compounds. We presented here ligand-based classical QSAR study involving the leishmanicidal activity of quinoxaline derivatives and molecular descriptors of diverse nature, aimed to understand their molecular activities from a quantitative point of view. Additionally, the cytotoxic activity of the compounds was also modeled in a QSTR approach, in order to help the design of more active and safe leishmanicidal compounds. Methods: Geometry optimizations were performed by semiempirical and DFT quantum-chemical methods. Molecular descriptors were calculated by E-Dragon online platform and submitted to a variable selection procedure, using Ordered Predictors Selector algorithm. The best QSAR and QSTR models were selected by MLR modeling and structure-activity relationships were considered, in accordance to the successful of the validation parameters. Results: For leishmanicidal activity, five descriptors were selected as the most important, providing a robust and predictive QSAR model via Multiple Linear Regression (MLR) (R2 = 0.71, Qloo 2 = 0.60, Qext 2 = 0.76 and rtest = 0.87). On the other hand, cytotoxicity was better related to seven descriptors in QSTR approach (R2 = 0.77, Qloo 2 = 0.65, Qext 2 = 0.85 and rtest = 0.92). Analysis of descriptors influences on both activities revealed that there are common features that could be explored to provide a most leishmanicidal and less cytotoxic compound, at the same time, in order to design more active and safe compounds. Conclusion: In establishing of the structure-activity relationships and interpreting the physical sense of the descriptors, we can conclude that molecules containing sulfoxyl, sulfonyl and halogens tend to be most active, but molecules with large volumes and electronegative atoms tend to be less active. In addition, in a very interesting way, we could observe that small molecules containing sulfoxyl, sulfonyl and halogens tend to be less cytotoxic and larger molecules with fewer atoms of greater mass and electronegativity than carbon tend to be more cytotoxic. Fortunately, the combination of these characteristics can be explored in the synthesis and evaluation of new safe derivatives with better leishmanicidal profile.