D-glucose-conjugated thioureas containing 2-aminopyrimidine as potential multitarget inhibitors for type 2 diabetes mellitus: Synthesis and biological activity study.

α-d-Glucose-conjugated thioureas 8a-w of substituted 4,6-diaryl-2-aminopyrimindines were designed, synthesized, and screened for their antidiabetic inhibitory activity. The thioureas with the strongest potential inhibitory activity included 8f (IC50 = 11.32 ± 0.34 μM for α-amylase), 8g (IC50 = 10.35 ± 0.88 μM for α-glucosidase), 8e (IC50 = 2.53 ± 0.03 nM for DPP-4), and 8c (IC50 = 3.93 ± 0.03 nM for PTP1B). The inhibitors 8g, 8e, and 8c were competitive α-glucosidase, non-competitive DDP-4, and non-competitive PTP1B inhibitors, respectively. In addition, compounds 8a, 8c, 8e, 8f, 8g, 8h, and 8j were noncytotoxic for 3T3 cell line. Induced fit docking study showed the key active interactions of each ligand with residues in the active site of each of these enzymes. Molecular dynamics simulation study on the representative complexes 8f/4W93 and 8e/3W2T in enzymes 4W93 and 3W2T, respectively, displayed the bioactive interactions between the residues and the corresponding potent inhibitor in the active site. Some of the various effects of the electron-donating and electron-withdrawing substituents on benzene of pyrimidine ring to inhibitory activities against enzymes related to T2DM were discussed. The calculations based on MM-GBSA showed the effects of the solvation to the active binding of the specific ligand in the active pocket of an enzyme.