Antidiabetic Potential of Novel 1,3,5-Trisubstituted-2-Thioxoimidazloidin-4-One Analogues: Insights into α-Glucosidase, α-Amylase, and Antioxidant Activities

Salma M Khirallah; Heba M M Ramadan; Hossam Aladl Aladl Aladl; Najla O Ayaz; Lina A F Kurdi; Mariusz Jaremko; Samar Zuhair Alshawwa; Essa M Saied

doi:10.3390/ph15121576

Antidiabetic Potential of Novel 1,3,5-Trisubstituted-2-Thioxoimidazloidin-4-One Analogues: Insights into α-Glucosidase, α-Amylase, and Antioxidant Activities

Pharmaceuticals (Basel). 2022 Dec 17;15(12):1576. doi: 10.3390/ph15121576.

Authors

Salma M Khirallah¹, Heba M M Ramadan², Hossam Aladl Aladl Aladl³, Najla O Ayaz⁴, Lina A F Kurdi⁵, Mariusz Jaremko⁶, Samar Zuhair Alshawwa⁷, Essa M Saied^{8

9}

Affiliations

¹ Biochemistry Department, Faculty of Science, Port Said University, Port Said 42526, Egypt.
² Chemistry Department, Faculty of Science, Port Said University, Port Said 42526, Egypt.
³ Department of Internal Medicine, Faculty of Medicine, AL-Azhar University, Nasr City, Cairo 11651, Egypt.
⁴ Department of Biochemistry, College of Science, University of Jeddah, Jeddah 80327, Saudi Arabia.
⁵ Department of Biology, College of Science, University of Jeddah, Jeddah 80327, Saudi Arabia.
⁶ Smart-Health Initiative and Red Sea Research Center, Division of Biological and Environmental Sciences and Engineering, King Abdullah University of Science and Technology, Thuwal 23955, Saudi Arabia.
⁷ Department of Pharmaceutical Sciences, College of Pharmacy, Princess Nourah bint Abdulrahman University, P.O. Box 84428, Riyadh 11671, Saudi Arabia.
⁸ Chemistry Department, Faculty of Science, Suez Canal University, Ismailia 41522, Egypt.
⁹ Institute for Chemistry, Humboldt Universität zu Berlin, Brook-Taylor-Str. 2, 12489 Berlin, Germany.

Abstract

As the ninth leading cause of death globally, diabetes mellitus (DM) is considered to be the worst chronic metabolic disease requiring an enormous need for healthcare with over 578 million expected cases by 2023. Several recent findings have demonstrated that mediating the activity of carbohydrate-hydrolyzing enzymes, including α-amylase and α-glucosidase, could be a potential strategy for managing the development of DM. In the presented study, a novel set of 1,3,5-trisubstituted-2-thioxoimidazolidin-4-ones was designed, synthesized, and characterized. The antidiabetic activity of the synthesized compounds was explored by assessing their inhibitory activity toward α-amylase and α-glucosidase enzymes. The results demonstrated that this class of compounds exhibits considerable inhibitory activity toward both α-amylase and α-glucosidase enzymes. Among the synthesized compounds, compound 5a demonstrated the most inhibitory activity with IC₅₀ of 5.08 and µg/mL and 0.21 µg/mL toward α-glucosidase and α-amylase activities, respectively, as compared to the drug Acarbose (IC₅₀ = 5.76 µg/mL and 0.39 µg/mL, respectively). To gain insights into the antidiabetic potential of compound 5a, we assessed the cytotoxic and antioxidant activities. Our findings indicated that compound 5a displays considerable cytotoxicity toward WI-38 cells with an IC₅₀ of 88.54 µg/mL, as compared to the drug Celecoxib (IC₅₀ = 93.05 µg/mL). Further, compound 5a exhibited a high scavenging activity toward 2,2-Diphenyl1-picrylhydrazyl (DPPH) free radicals (IC₅₀ = 51.75 µg/mL) and showed a low potential to produce ROS as indicated by the monitoring of the generated H₂O₂ (132.4 pg/mL), as compared to Trolox (IC₅₀ = 58.09 µg/mL) and Celecoxib (171.6 pg/mL). Finally, we performed extensive molecular modeling studies to affirm the binding affinity of this class of compounds to the binding pocket of α-amylase and α-glucosidase enzymes. Collectively, our findings indicate that this class of compounds, particularly compound 5a, could be utilized as a lead structure for the development of novel compounds with potential antidiabetic and antioxidant activities.

Keywords: antidiabetic activity; antioxidant activity; cytotoxicity; diabetes mellitus; molecular docking simulation; substituted-2-thiohydantoins; α-amylase activity; α-glucosidase activity.

Grants and funding

This research was funded by the Faculty of Science, Port Said University and Suez Canal University, Egypt. This research was also funded by Princess Nourah bint Abdulrahman University Researchers Supporting Project number (PNURSP2022R165), Princess Nourah bint Abdulrahman University, Riyadh, Saudi Arabia. The research was also supported by the Faculty of Medicine, Al-Azhar University, Egypt.