Synthesis, molecular docking, ctDNA interaction, DFT calculation and evaluation of antiproliferative and anti- Toxoplasma gondii activities of 2,4-diaminotriazine-thiazole derivatives.

Synthesis, characterization, and investigation of antiproliferative activities against human cancer cell lines (MV4-11, MCF-7, and A549) and Toxoplasma gondii parasite of twelve novel 2,4-diaminotriazine-thiazoles are presented. The toxicity of the compounds was studied at three different cell types, normal mouse fibroblast (Balb/3T3), mouse fibroblast (L929), and human VERO cells. The structures of novel compounds were determined using 1 H and 13 C NMR, FAB(+)-MS, and elemental analyses. Among the derivatives, 4a - k showed very high activity against MV4-11 cell line with IC50 values between 1.13 and 3.21 µg/ml. Additionally, the cytotoxic activity of compounds 4a - k against normal mouse fibroblast Balb/3T3 cells is about 20-100 times lower than against cancer cell lines. According to our results, compounds 4a , 4b , 4d , and 4i have very strong activity against human breast carcinoma MCF-7, with IC50 values from 3.18 to 4.28 µg/ml. Moreover, diaminotriazines 4a - l showed significant anti- Toxoplasma gondii activity, with IC50 values 9-68 times lower than those observed for sulfadiazine. Molecular docking studies indicated DNA-binding site of hTopoI and hTopoII as possible anticancer targets and purine nucleoside phosphorylase as possible anti -toxoplasmosis target. Our UV-Vis spectroscopic results indicate also that diaminotriazine-thiazoles tends to interact with DNA by intercalation. Additionally, the structure and the interaction and binding energies of a model complex formed by compound 4a and two thymine molecules are investigated using quantum mechanical methods.