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  3. Exploring dihydropyrimidone derivatives as modulators of carbohydrate catabolic enzyme to mitigate diabetes

Exploring dihydropyrimidone derivatives as modulators of carbohydrate catabolic enzyme to mitigate diabetes

  • Sci Rep. 2024 Dec 30;14(1):31761. doi: 10.1038/s41598-024-82765-1.
Syed Parween Ali 1,  Farheen Mansoor 2,  Shaymaa Fadhel Abbas Albaayit 3,  Farman Ali 4,  Ayed A Dera 1,  Muhammad Shahbaz 5 6,  Jawad Ullah 7,  Hailah M Almohaimeed 8,  Reem M Gahtani 1,  Ahmed M Abdulfattah 9 10,  Fahad M Alshabrmi 11,  Sarfaraz Alam 12,  Saeed Ullah 13
Affiliations

Affiliations

  • 1 Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, King Khalid University, Abha, 62529, Saudi Arabia.
  • 2 Dr. Panjwani Center for Molecular Medicine and Drug Research, International Center for Chemical and Biological Sciences, University of Karachi, Karachi, 75270, Pakistan.
  • 3 Department of Biology, College of Science, University of Baghdad, Baghdad, Iraq. shaymaa_albaayit@yahoo.com.
  • 4 Department of Chemistry, Federal Urdu University of Arts, Sciences and Technology, Karachi, 75300, Pakistan.
  • 5 Faculty of Chemistry, Jagiellonian University, Gronostajowa 2, Krakow, 30-387, Poland.
  • 6 School of Exact and Natural Sciences, Jagiellonian University, Łojasiewicza 11, Krakow, 30-348, Poland.
  • 7 Department of Chemistry, Hazara University, Mansehra, 21120, Pakistan.
  • 8 Department of Basic Science, College of Medicine, Princess Nourah bint Abdulrahman University, P.O.Box 84428, Riyadh, 11671, Saudi Arabia.
  • 9 Department of Medial Laboratory Sciences, Faculty of Applied Medical Science, King Abdulaziz University, Jeddah, 2158, Saudi Arabia.
  • 10 Embryonic Stem Cell Unit, King Fahd Medical Research Center, King Abdulaziz University, Jeddah, 21589, Saudi Arabia.
  • 11 Department of Medical Laboratories, College of Applied Medical Sciences, Qassim University, Buraydah, 51452, Saudi Arabia.
  • 12 Tunneling Group, Biotechnology Centre, Silesian University of Technology, Gliwice, 44-100, Poland. malam@polsl.pl.
  • 13 Natural and Medical Sciences Research Center, University of Nizwa, P.O. Box 33, PC 616, Birkat Al Mauz, Nizwa, Sultanate of Oman. ahmedsaeedkhan872@gmail.com.
PMID: 39738505 DOI: 10.1038/s41598-024-82765-1
Abstract

Diabetes is a prevalent and serious metabolic disorder affecting millions globally, and it poses extensive health risks due to elevated blood glucose levels. One promising approach for managing diabetes is the inhibition of α-glucosidase, an enzyme that plays a crucial role in carbohydrate metabolism. Targeting α-glucosidase can help delay glucose absorption, thus controlling postprandial blood sugar spikes. Dihydropyrimidones, a core structural class present in various biologically active natural compounds, have been recognized for their diverse therapeutic potential, including anti-diabetic properties. In this study, we evaluated a library of previously synthesized 37 Dihydropyrimidone derivatives to assess their potential as α-glucosidase inhibitors. We identified 34 derivatives with significant inhibitory activity, exhibiting IC50 values in the range of 5.30-56.72 µM. Among these, compounds 2, 4-7, 9-11, 13-16, 31, 32, and 33 demonstrated high potency, with IC50 values below 20 µM; the most active compound, 5, achieved an IC50 of 5.30 µM. A detailed kinetic study on compound 5 revealed a competitive inhibition mode with a Ki value of 16.10 ± 0.0075 µM. Additionally, cytotoxicity assays confirmed that compound 5 is non-toxic to BJ cell lines, underscoring its safety for therapeutic use. The computational studies further supported the inhibitory potential by illustrating key interactions and binding affinities between the Dihydropyrimidone derivatives and the α-glucosidase, highlighting these compounds as promising candidates for diabetes management.

Keywords

Diabetes therapy; Dihydropyrimidone; Kinetics; Molecular docking simulation; Non-cytotoxicity; α-Glucosidase inhibition.

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