Design, synthesis, characterization, in silico, in vitro and in vivo antidiabetic studies of novel benzothiophene derivatives

Abstract

This study evaluated the antidiabetic efficacy of novel benzothiophenes using in silico, in vitro and in vivo methods. The synthesis of benzo[b]thiophene-2-carbohydrazide, specifically the Schiff base of benzo[b]thiophene (2, 3, 6) and the 1,3,4-oxadiazole adducts (4, 5, and 7) was performed through a cyclization reaction of the corresponding intermediates, compounds 2, 3 and 6. The cyclization was carried out by reacting the hydrazones (2, 3 and 6) with copper triflate (Cu(OTf)₂) as the catalyst and potassium carbonate (K₂CO₃) as a base in polar solvents such as N, N-dimethylformamide (DMF). The identity of these compounds was confirmed through comprehensive spectroscopic characterization, including infrared (IR) spectroscopy, carbon-13 nuclear magnetic resonance (¹³C NMR), proton nuclear magnetic resonance (¹H NMR), and high-resolution mass spectrometry (HRMS). Molecular docking, molecular dynamics simulation (200 ns), density functional theory (B3LYP, 6-31G), ADMET, and in vitro α-amylase inhibitory studies of the synthesized benzothiophenes were conducted. Also, the antihyperglycaemic activity of the top-ranked benzothiophenes was evaluated in glucose-loaded mice. Extensive structural characterization of the synthesized Schiff bases and oxadiazole adducts was performed. The molecular docking studies identified the synthesized compounds as potential α-amylase inhibitors, with binding affinities of -9.0, -8.5, and − 8.1 kcal/mol, respectively. Quantum chemical and ADMET studies further indicated the compounds as promising drug candidates. The in vitro inhibitory studies showed that 4 demonstrated the lowest IC₅₀ value of 0.032 µM compared to 2 (0.035 µM) and acarbose (0.09 µM). Comprehensive toxicity and histological studies of the compounds are recommended for further studies. (2 and 4) elicited good α-amylase inhibitory potential with IC₅₀ values of 0.035 and 0.032 µM.