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

被引：19

作者：

Ullah, Saeed ^{[1
]}

Waqas, Muhammad ^{[1
,2
]}

Halim, Sobia Ahsan ^{[1
]}

Khan, Imtiaz ^{[3
,4
]}

Khalid, Asaad ^{[5
]}

Abdalla, Ashraf N. ^{[6
]}

Makeen, Hafiz A. ^{[7
]}

Ibrar, Aliya ^{[8
]}

Khan, Ajmal ^{[1
]}

Al-Harrasi, Ahmed ^{[1
]}

机构：

[1] Univ Nizwa, Nat & Med Sci Res Ctr, Nizwa 616, Oman

[2] Hazara Univ Mansehra, Dept Biotechnol & Genet Engn, Mansehra 21120, Pakistan

[3] Univ Manchester, Dept Chem, 131 Princess St, Manchester M1 7DN, England

[4] Univ Manchester, Manchester Inst Biotechnol, 131 Princess St, Manchester M1 7DN, England

[5] Jazan Univ, Subst Abuse & Toxicol Res Ctr, POB 114, Jazan 45142, Saudi Arabia

[6] Umm Al Qura Univ, Coll Pharm, Dept Pharmacol & Toxicol, Mecca 21955, Saudi Arabia

[7] Jazan Univ, Fac Pharm, Clin Pharm Dept, Pharm Practice Res Unit, Jazan, Saudi Arabia

[8] Univ Haripur, Dept Chem, Fac Phys & Appl Sci, Haripur 22620, Kpk, Pakistan

来源：

INTERNATIONAL JOURNAL OF BIOLOGICAL MACROMOLECULES | 2023年 / 250卷

关键词：

Triazolothiadiazole; Triazolothiadiazine; alpha-Glucosidase; Postprandial hyperglycaemia; Molecular docking; Molecular dynamics simulations; CRYSTAL-STRUCTURE; MICROBIOME; CHOLINESTERASE; PARAMETERS; SOFTWARE; LIBRARY; COMPLEX;

D O I：

10.1016/j.ijbiomac.2023.126227

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

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, alpha-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 alpha-glucosidase inhibitory activities (IC50 in the range of 2.44-219.93 mu M) as compared to marketed drug, acarbose (IC50 = 873.34 +/- 1.67 mu M). 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 alpha-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 alpha-glucosidase. Both docking and simulation results favored our in vitro mechanistic analysis.

引用

页数：16

共 59 条

[1] Synthesis, crystal structure and Hirshfeld Surface analysis of benzamide derivatives of thiourea as potent inhibitors of α-glucosidase in-vitro [J].