DPP-4 x PTP1B

Benzoic acid, a versatile aromatic carboxylic acid, has gained attention as a promising scaffold for developing therapeutic agents targeting diabetes mellitus, a chronic metabolic disorder characterized by persistent hyperglycemia and associated complications. Structural analysis elucidated how modifications to the benzoic acid structure enhance pharmacological efficacy by influencing glucose metabolism, insulin sensitivity, and oxidative stress pathways. Notably, benzoic acid derivatives exhibit inhibitory effects on key enzymes such as protein tyrosine phosphatase 1B (PTP1B), dipeptidyl peptidase-4 (DPP-4), α-glucosidase, peroxisome proliferator-activated receptor gamma (PPAR-γ), and aldose reductase, which are implicated in diabetes pathophysiology. Molecular docking simulations further reveal the molecular interactions underlying these effects, supporting the potential of these derivatives in multi-targeted therapies. This review integrates findings from SAR studies of benzoic acid synthesized over two decades, showcasing significant advancements in the design and development of benzoic acid derivatives as promising candidates for the effective management of diabetes and its associated complications.

Paeonia emodi has long been used in folk medicine to treat a variety of ailments, including diabetes, skin disorders, dropsy, cuts, wounds, ulcers, fever, and blood disorders, etc., which are generally categorized under the complications of diabetes mellitus. Various species of this genus have also been verified to possess strong anti‐diabetic activity. In this context, the current study was designed to investigate the antidiabetic potential to confirm the purported traditional use of P. emodi . Different solvent fractions of P. emodi , i.e., crude methanolic extract (Pe.Cr), n‐hexane (Pe.Hex), chloroform (Pe.Chf), ethyl acetate (Pe.EtAc), butanol (Pe.Bt) and aqueous (Pe.Aq) were used for in vitro studies against α‐glucosidase, α‐ amylase, dipeptidyl peptidase‐4 (DPP‐4), and protein tyrosine phosphatase 1B (PTP‐1B) using a spectrophotometer and microplate reader. Among all fractions, Pe.Bt had the most prominent activity and was subjected to GC–MS analysis, in vivo anti‐diabetic, pancreas protective, and hepatoprotective studies in alloxan‐induced diabetes rats. The animals administered with alloxan (except group1) having FBGL higher than 220 mg/dL were selected and placed in different groups. The first group, which served as a normal control, received normal saline. The second group received a 5% tween‐80 suspension, which served as diabetic control. The 3rd, 4th and 5th groups were administered Pe.Bt at the doses of 150, 300, and 500 mg/kg body weight, respectively, through oral gavage. Group six received metformin 50 mg/kg and served as the standard group. Fasting Blood glucose level (FBGL) was checked for 21 days. Liver function tests, insulin level, hepatoprotection, and pancreas protection study were investigated. The α‐glucosidase was inhibited effectively by Pe.Bt with an IC 50 value of 626 μg/mL. The antioxidant activities also substantiated the excellent inhibitory potential of Pe.Bt. The IC 50 value of Pe.Bt against DPPH and ABTS was figured out to be 77 and 139 μg/mL, respectively, which was relatively comparable with ascorbic acid. Similarly, Pe.Bt was found active against PTP‐1B and showed a moderate effect against DPP4 with IC 50 of 45.13 and 92.45, respectively. In the time frame of 21 days, the metformin and Pe.Bt significantly decreased FBGL on the 21st day to 108 and 96 mg/dL, respectively. Similarly, rats treated with Pe.Bt (500 mg/kg) significantly lowered the level of alanine transaminase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP) and increased total protein level (TP) in comparison with the diabetic control group. The histopathological study revealed that rats treated with Pe.Bt (500 mg/kg) have a remarkable ameliorative effect on liver and pancreas histological architecture as compared to the diabetic control group. The findings of the current investigations indicated that Pe.Bt possesses strong anti‐diabetic, hepatoprotective, anti‐oxidant properties and alleviates alloxan‐induced pancreatic damage in diabetic rats.

Type 2 diabetes mellitus (T2-DM) is associated with several dysfunctions and complications. In this study, different chalcones (1a-c) were synthesized through the condensation of acetylacetone with different aromatic aldehydes in a basic medium. These chalcones were then used as key synthons for the synthesis of new pyrimidine derivatives (2a-c) through a reaction with metformin (MTF). Elemental analysis and spectroscopic techniques, such as FT-IR, ¹H NMR, and ¹³C NMR were used to confirm the structures of the compounds. The compounds were then evaluated for their antidiabetic activities in vitro and in vivo. In vitro assays included glucose uptake, α-amylase, and α-glucosidase inhibition were performed. Fifty-four rats were equally divided into 9 groups: Gp1 served as a negative control; Gp2 as the T2-DM group; Gp3 was T2-DM group that were treated with MTF (100 mg/Kg); from Gp4 to Gp9 were T2-DM groups that were treated with chalcones (1a-c) and pyrimidine (2a-c) compounds (100 mg/Kg), respectively. Pharmacokinetic properties were analyzed by using the ADMET lab 2.0 web server and molecular docking studies were conducted using AutoDock Vina. Compound 1a exerted the strongest affinity with α-glucosidase, compound 2c demonstrated strong binding for dipeptidyl peptidase 4 and protein tyrosine phosphatase 1B with energy of -9.7, and -7.7 kcal/mol, respectively. The effect of MTF modified compounds demonstrated significant improvement in glucose consumption by cells, with compounds 1c and 2c had the strongest uptake activities in vitro. Significant inhibitory effects against α-amylase and α-glucosidase were recorded by 1a, 1c and 2c compounds. In vivo studies with streptozotocin-induced diabetic rats revealed 1c and 2c have shown significant antidiabetic activities.