Journal Article Ahead of print
PubMed: 42925716 DOI: 10.1016/j.bioorg.2026.110667
Aniline-linked coumarin-triazole hybrids as α-glucosidase inhibitors: An insightful study from synthesis to in vivo efficacy and mechanistic analysis.
Bioorg Chem 184:110667
Authors: Bahareh Bayati, Mahdis Sadeghi Moghadam, Fariba Peytam, Mahmood Biglar, Zahra Emamgholipour, Somayeh Mojtabavi, Elmira Meghrazi Ahadi, Maryam Norouzbahari, Hayrettin Ozan Gülcan, Fahimeh Ghasemi, Seyed Esmaeil Sadat-Ebrahimi, Maliheh Barazandeh Tehrani, Vahid Sheibani, Loghman Firoozpour, Alireza Foroumadi
Affiliations
- Drug Design and Development Research Center, The Institute of Pharmaceutical Sciences (TIPS), Tehran University of Medical Sciences, Tehran, Iran; Department of Medicinal Chemistry, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran.
- Department of Medicinal Chemistry, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran.
- Drug Design and Development Research Center, The Institute of Pharmaceutical Sciences (TIPS), Tehran University of Medical Sciences, Tehran, Iran.
- Department of Pharmaceutical Biotechnology, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran.
- Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Eastern Mediterranean University, Famagusta, TRNC, via Mersin, 10, Turkey.
- Department of Bioinformatics and Systems Biology, School of Advanced Technologies in Medicine, Tehran University of Medical Sciences, Tehran, Iran.
- Neuroscience Research Center, Institute of Neuropharmacology, Kerman University of Medical Sciences, Kerman, Iran.
- Drug Design and Development Research Center, The Institute of Pharmaceutical Sciences (TIPS), Tehran University of Medical Sciences, Tehran, Iran; Department of Medicinal Chemistry, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran.
Abstract
A new series of coumarin-aniline-triazole hybrids 12a-p was prepared using a multi-step approach. This synthesis involved a Knoevenagel condensation between 2-hydroxybenzaldehyde and diethyl malonate, followed by ester hydrolysis and amide coupling to yield a coumarin-based alkyne, which was then reacted with various 2-azido-N-arylacetamides via a click reaction. All synthesized compounds were evaluated for their potential antidiabetic activities through α-glucosidase inhibition, possessing remarkably superior potency compared to the reference drug acarbose (IC 50 = 750.0 ± 0.8 μM), with IC 50 values ranging from 1.1 to 44.2 μM. Among them, the 2-methyl derivative 12b emerged as the most potent, exhibiting approximately 750-fold greater activity than acarbose. Kinetic studies established that 12b was a competitive inhibitor (Kᵢ = 1700 nM), and selectivity assays confirmed its excellent specificity for α-glucosidase over α-amylase (no activity was observed up to 100 μM), suggesting a reduced risk of gastrointestinal side effects. Spectral investigations using circular dichroism (CD) spectroscopy revealed that 12b induced significant conformational rearrangements in the enzyme, characterized by a noticeable increase in β-sheet content (from 32.3% to 81.3%), while fluorescence spectroscopy confirmed a 1:1 binding stoichiometry with high affinity (K a = 1.75 × 10 5 L mol -1 at 25 °C) and an enthalpy-driven binding mechanism (ΔH = -39.19 kJ mol -1, ΔS = -31.07 J mol -1 K -1). In vivo studies in a streptozotocin-induced diabetic rat model demonstrated that, while compound 12b at 30 mg/kg exhibited significant antihyperglycemic activity (55% reduction in FBG), its efficacy was slightly lower than that of acarbose (62% reduction in FBG). Additionally, histopathological examination confirmed dose-dependent protective effects against diabetes-induced hepatic and pancreatic damage. Molecular docking and dynamics simulations also provided structural insights into the stable binding of 12b within the α-glucosidase active site (with a mean binding energy of -10.02 kcal/mol), establishing persistent hydrogen-bonding interactions with key residues, particularly ARG439 and LYS155. Collectively, these findings represent compound 12b as a promising lead candidate for further optimization and development as a safe and effective α-glucosidase inhibitor for the management of type 2 diabetes.
MeSH
Diabetes Mellitus, Acarbose, Biochemistry, Triazoles, Glucosidases, Amides