Quantitative structure-activity relationship study and directed synthesis of Thieno[2,3-d]pyrimidine-2,4-diones as monocarboxylate transporter 1 inhibitors

The aim of any quantitative structure-activity relationship (QSAR) study is not only to reveal relationships between structure of molecules and their biological activity, but also to explain it within the bounds of theoretical conceptions and to use the obtained model for prediction of properties of new compounds. That provides possibility to execute directed synthesis of new compounds with required biological activities. Monocarboxylate transporter 1 (MCT1) is one of the targets in a search for new immune response modulating and antitumor agents. In the present study, QSAR model for MCT1 binding affinity is developed. Decisive influence of relative negative partial charge, solvation energy, and radius of gyration on MCT1 inhibition has been detected. Theoretical explanation of the obtained model is given, and biological activity prediction for a series of N-vinyl derivatives of thieno[2,3-d]pyrimidine-2,4-dione is made. Directed synthesis of three leading compounds has been executed according to prediction results.