Multifaceted bioactivity of thiosemicarbazide derivatives: Synthesis, characterization, and DFT investigations on inhibition of α-amylase, hydroxyl radical scavenging, and iron chelating activities with molecular docking insights

Abstract

In this study, eight bioactive thiosemicarbazide derivatives (3a-h) were synthesized and characterized through 1HNMR , 13CNMR and Mass spectroscopic techniques. Finally, their inhibition activities against α-amylase and antioxidant activity were investigated. Among the synthetic series, five compounds 3 g (IC50 = 8.61 ± 1.42 µM) 3a (IC50 = 13.41 ± 1.65 µM), 3e (IC50 = 15.23 ± 1.17 µM), 3 h (IC50 = 17.37 ± 0.87 µM) and 3d (IC50 = 17.95 ± 1.99 µM) showed excellent inhibition by comparing with standard (acarbose, IC50 = 21.55 ± 1.31 µM). Similarly, in the case of iron chelating agent activity, product compounds 3a-h presented outstanding activity in the range of IC50 = 18.19 ± 1.81 to 63.42 ± 1.45 µM superior than standard (EDTA, IC50 = 66.43 ± 1.07 µM) while in hydroxyl radical scavenging activity all the synthesized products 3a-h also showed excellent scavenging activity in the range of IC50 values 25.85 ± 1.13 to 58.9 ± 2.95 µM when compared to standard vitamin C (IC50 = 60.51 ± 1.02 µM). We expanded our investigation to molecular interactions via a docking study, where these compounds were docked with the target protein to unveil their binding affinities and key interactions, offering additional insights into their inhibitory mechanisms. The chemical nature of the synthesized compounds was revealed through density functional theory (DFT) calculations at B3LYP/6–311++G(d,p). Intramolecular hydrogen bonding was explored using DFT-d3 and reduced density gradient (RDG) analysis. Additionally, various reactivity parameters were investigated through TD-DFT at the CAM-B3LYP/6–311++G(d,p) method.