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

Barakat A 1 , Islam MS 2 , Al-Majid AM 3 , Ghabbour HA 4 , Fun HK 5 , Javed K 6 Show all authors , Imad R 7 , Yousuf S 6 , Choudhary MI 8 , Wadood A 9

Affiliations 

  • 1 Department of Chemistry, College of Science, King Saud University, PO Box 2455, Riyadh 11451, Saudi Arabia; Department of Chemistry, Faculty of Science, Alexandria University, PO Box 426, Ibrahimia, 21321 Alexandria, Egypt. Electronic address: ambarakat@ksu.edu.sa
  • 2 Department of Chemistry, College of Science, King Saud University, PO Box 2455, Riyadh 11451, Saudi Arabia. Electronic address: shahid.10amui@gmail.com
  • 3 Department of Chemistry, College of Science, King Saud University, PO Box 2455, Riyadh 11451, Saudi Arabia
  • 4 Department of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, PO Box 2457, Riyadh 11451, Saudi Arabia
  • 5 Department of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, PO Box 2457, Riyadh 11451, Saudi Arabia; X-ray Crystallography Unit, School of Physics, Universiti Sains Malaysia, Penang 11800, Malaysia
  • 6 H.E.J. Research Institute of Chemistry, International Center for Chemical and Biological Sciences, University of Karachi, Karachi 75270, Pakistan
  • 7 Dr. Panjwani Center for Molecular Medicine and Drug Research, International Center for Chemical and Biological Sciences, University of Karachi, Karachi 75270, Pakistan
  • 8 Department of Chemistry, College of Science, King Saud University, PO Box 2455, Riyadh 11451, Saudi Arabia; H.E.J. Research Institute of Chemistry, International Center for Chemical and Biological Sciences, University of Karachi, Karachi 75270, Pakistan
  • 9 Department of Biochemistry, Abdul Wali Khan University, Mardan 23200, Pakistan
Bioorg Med Chem, 2015 Oct 15;23(20):6740-8.
PMID: 26381063 DOI: 10.1016/j.bmc.2015.09.001

Abstract

We describe here the synthesis of dihydropyrimidines derivatives 3a-p, and evaluation of their α-glucosidase enzyme inhibition activities. Compounds 3b (IC50=62.4±1.5 μM), 3c (IC50=25.3±1.26 μM), 3d (IC50=12.4±0.15 μM), 3e (IC50=22.9±0.25 μM), 3g (IC50=23.8±0.17 μM), 3h (IC50=163.3±5.1 μM), 3i (IC50=30.6±0.6 μM), 3m (IC50=26.4±0.34 μM), and 3o (IC50=136.1±6.63 μM) were found to be potent α-glucosidase inhibitors in comparison to the standard drug acarbose (IC50=840±1.73 μM). 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±0.30 μM), 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.

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