Thiourea derivatives inhibit key diabetes-associated enzymes and advanced glycation end-product formation as a treatment for diabetes mellitus

This study was designed to screen novel thiourea derivatives against different enzymes, such as alpha-amylase, alpha-glucosidase, protein tyrosine phosphatase 1 B, and advanced glycated end product (AGEs). A cytotoxicity analysis was performed using rat L6 myotubes and molecular docking analysis was performed to map the binding interactions between the active compounds and alpha-amylase and alpha-glucosidase. The data revealed the potency of five compounds, including E (1-(2,4-difluorophenyl)-3-(3,4-dimethyl phenyl) thiourea), AG (1-(2-methoxy-5-(trifluoromethyl) phenyl)-3-(3-methoxy phenyl) thiourea), AF (1-(2,4-dichlorophenyl)-3-(4-ethylphenyl) thiourea), AD (1-(2,4-dichlorophenyl)-3-(4-ethylphenyl) thiourea), and AH (1-(2,4-difluorophenyl)-3-(2-iodophenyl) thiourea), showed activity against alpha-amylase. The corresponding percentage inhibitions were found to be 85 & PLUSMN; 1.9, 82 & PLUSMN; 0.7, 75 & PLUSMN; 1.2, 72 & PLUSMN; 0.4, and 65 & PLUSMN; 1.1%, respectively. These compounds were then screened using in vitro assays. Among them, AH showed the highest activity against alpha-glucosidase, AGEs, and PTP1B, with percentage inhibitions of 86 & PLUSMN; 0.4% (IC50 = 47.9 mu M), 85 & PLUSMN; 0.7% (IC50 = 49.51 mu M), and 85 & PLUSMN; 0.5% (IC50 = 79.74 mu M), respectively. Compound AH showed an increased glucose uptake at a concentration of 100 mu M. Finally, an in vivo study was conducted using a streptozotocin-induced diabetic mouse model and PTP1B expression was assessed using real-time PCR. Additionally, we examined the hypoglycemic effect of compound AH in diabetic rats compared to the standard drug glibenclamide.