Triazolothiadiazoles and triazolothiadiazines as potent α-glucosidase inhibitors: Mechanistic insights from kinetics studies, molecular docking and dynamics simulations

• Published in: International journal of biological macromolecules 2023-10, Vol.250, p.126227-126227, Article 126227
• Main Authors: Ullah, Saeed, Waqas, Muhammad, Halim, Sobia Ahsan, Khan, Imtiaz, Khalid, Asaad, Abdalla, Ashraf N., Makeen, Hafiz A., Ibrar, Aliya, Khan, Ajmal, Al-Harrasi, Ahmed
• Format: Article
• Language: English
• Subjects: Molecular docking; Molecular dynamics simulations; Postprandial hyperglycaemia; Triazolothiadiazine; Triazolothiadiazole; α-Glucosidase
• ISSN: 0141-8130; 1879-0003
• DOI: 10.1016/j.ijbiomac.2023.126227

Diabetes mellitus has been considered as a serious health problem worldwide due its high prevalence rate and associated complications. In this context, the current research work aims at exploring new structural leads for the treatment of a major metabolic disorder, diabetes mellitus type 2. The outcomes of our prior studies on a diverse set of triazolothiadiazole and triazolothiadiazine derivatives and their therapeutic potential, encouraged us to explore their anti-diabetic competency by targeting the key carbohydrate catabolic enzyme, α-glucosidase. Therefore, all these analogues were examined to reveal their contribution towards this severe metabolic issue. Interestingly, all the tested compounds (2a-2l and 3a-3p) exhibited several times more potent α-glucosidase inhibitory activities (IC50 in the range of 2.44–219.93 μM) as compared to marketed drug, acarbose (IC50 = 873.34 ± 1.67 μM). Furthermore, their mechanism of action was investigated through in vitro kinetics studies which revealed compounds 3a, 3d, 3o, and 2k as competitive inhibitors, and 3f as a mixed type inhibitor of α-glucosidase. In addition, in silico molecular docking and molecular dynamics simulations were applied to observe the mode of interaction of the active hits within the binding pocket of α-glucosidase. Both docking and simulation results favored our in vitro mechanistic analysis.