Synthesis, in vitro biological activities and in silico study of dihydropyrimidines derivatives

• Published in: Bioorganic & medicinal chemistry 2015-10, Vol.23 (20), p.6740-6748
• Main Authors: Barakat, Assem, Islam, Mohammad Shahidul, Al-Majid, Abdullah Mohammed, Ghabbour, Hazem A., Fun, Hoong-Kun, Javed, Kulsoom, Imad, Rehan, Yousuf, Sammer, Choudhary, M. Iqbal, Wadood, Abdul
• Format: Article
• Language: English
• Subjects: 3T3 Cells; alpha-Glucosidases - metabolism; Animals; Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Cancer cell lines; Cell Proliferation - drug effects; Computer Simulation; Cytotoxicity; Dose-Response Relationship, Drug; Drug Screening Assays, Antitumor; Glycoside Hydrolase Inhibitors - chemical synthesis; Glycoside Hydrolase Inhibitors - chemistry; Glycoside Hydrolase Inhibitors - pharmacology; HeLa Cells; Humans; MCF-7 Cells; Mice; Molecular docking; Molecular Docking Simulation; Molecular Structure; Pyrimidines; Pyrimidines - chemical synthesis; Pyrimidines - chemistry; Pyrimidines - pharmacology; Spiro heterocycles; Structure-Activity Relationship; Tumor Cells, Cultured; α-Glucosidase inhibitors
• ISSN: 0968-0896; 1464-3391
• DOI: 10.1016/j.bmc.2015.09.001

[Display omitted] We describe here the synthesis of dihydropyrimidines derivatives 3a–p, and evaluation of their α-glucosidase enzyme inhibition activities. Compounds 3b (IC50=62.4±1.5μM), 3c (IC50=25.3±1.26μM), 3d (IC50=12.4±0.15μM), 3e (IC50=22.9±0.25μM), 3g (IC50=23.8±0.17μM), 3h (IC50=163.3±5.1μM), 3i (IC50=30.6±0.6μM), 3m (IC50=26.4±0.34μM), and 3o (IC50=136.1±6.63μM) were found to be potent α-glucosidase inhibitors in comparison to the standard drug acarbose (IC50=840±1.73μM). The compounds were also evaluated for their in vitro cytotoxic activity against PC-3, HeLa, and MCF-3 cancer cell lines, and 3T3 mouse fibroblast cell line. All compounds were found to be non cytotoxic, except compounds 3f and 3m (IC50=17.79±0.66–20.44±0.30μM), which showed a weak cytotoxic activity against the HeLa, and 3T3 cell lines. In molecular docking simulation study, all the compounds were docked into the active site of the predicted homology model of α-glucosidase enzyme. From the docking result, it was observed that most of the synthesized compounds showed interaction through carbonyl oxygen atom and polar phenyl ring with active site residues of the enzyme.