Rational design of naphtho[2,3-d]imidazole-4,9-dione-linked 1,3,4-oxadiazoles as α-amylase inhibitors supported by QSAR, docking, molecular dynamics, and ADME approaches.

A new series of 1,3,4-oxadiazole derivatives linked to naphtho[2,3-d]imidazole-4,9-dione were designed, synthesized, and evaluated for their α-amylase inhibitory activity through both in vitro and in silico methods. The compounds were synthesized via cyclization of (E/Z)-N'-(aryl/heteroarylbenzylidene)-2-(4,9-dioxo-4,9-dihydro-1H-naphtho[2,3-d]imidazole-1-yl)acetohydrazides (8a-8aa) with iodobenzene diacetate (IBD) in dichloromethane (DCM). The structures of the synthesized compounds were confirmed using various spectroscopic techniques. The in vitro testing revealed that several derivatives, including 8e, 8f, 8g, 8h, 8i, and 8v, exhibited α-amylase inhibition comparable to the standard drug acarbose. Among these, 8v, having -OCH3 substitution at the meta and para positions, showed the most potent inhibition, with an IC50 = 17.29 ± 0.09 µg mL-1, whereas acarbose had an IC50 = 20.02 ± 0.02 µg mL-1. In contrast, compound 8a (IC50 = 28.04 ± 0.03 µg mL-1) demonstrated the weakest inhibitory effects. QSAR studies identified key molecular descriptors that correlate with improved inhibitory activity, aiding in the design of novel inhibitors. Molecular docking studies were conducted to explore the binding interactions of the compounds with the α-amylase active site, while molecular dynamics simulations over 100 ns were performed to assess the stability of the enzyme-inhibitor complexes. ADME analysis was also carried out to evaluate the pharmacokinetic properties and drug-likeness of the promising derivatives.