Anticancer evaluation of the selected tetrahydropyrimidines: 3D-QSAR, cytotoxic activities, mechanism of action, DNA, and BSA interactions

Abstract Selected tetrahydropyrimidines (THPMs) were investigated by means of cytotoxic activities on selected cancer (HeLa, A549, and LS174) and non-cancerous cell lines (MRC-5). Among evaluated compounds, two of them (B7 and B8) showed good cytotoxic activity on the tested cell lines and were selected for further evaluation that included mechanism of action, DNA and BSA interactions and molecular docking study. Calculated parameters from fluorescence quenching studies indicated that B7 and B8 bind on minor groove of DNA and have great ability to bind on carrier protein. Three-dimensional quantitative structure anti-HeLa activity study was performed with data set of THPMs. Molecular Interaction Fields were used to derive Grid independent descriptors (GRIND), as independent variables in Pentacle software. The quality and predictive capacity of the model was proved by internal statistical parameters: R2 = 0.992, Q2= 0.51, as well as external parameters such as R2 pred = 0.804 and rm2, r/ 2 m and r2 m, that were higher than 0.5. The structural determinants significant for anti-HeLa activity of compounds were identified by using developed 3D-QSAR model. Interpretation of the most impactful GRIND variables on the anti-HeLa activity generated several hypotheses for design of novel and more potent anti-HeLa tetrahydropyrimidines. Additional molecular targets for the most active synthesized derivatives (B7 and B8) are predicted by use of online web-based tool-SwissTargetPrediction.The authors are grateful to the Ministry of Education, Science and Technological Development of the Republic of Serbia for financial support (Agreements No: 451–03–9/2021–14/200122, 451–03–68/2022–14/200378, 451–03–9/2021–14/200161)