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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 IC
50
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 IC
50
values from 3.18 to 4.28 µg/ml. Moreover, diaminotriazines
4a
–
l
showed significant anti-
Toxoplasma gondii
activity, with IC
50
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.