Synthesis, alpha glycosidase activities and molecular docking study of novel 4-amino-2H-1,2,4-triazol-3(4H)-one Schiff base derivatives

Abstract

• for the first time the synthesis of novel 4-amino-2H-1,2,4-triazol-3(4H)-one and its Schiff base derivatives via modified Boulton–Katritzky method. • that these compounds were confirmed by 1 H-NMR and EIMS spectroscopy. • the comprehensive Structure-Activity Relationship (SAR) of the 4-amino-2H-1,2,4-triazol-3(4H)-one and its Schiff base derivatives. • α-glucosidase inhibition assay of the 4-amino-2H-1,2,4-triazol-3(4H)-one and its novel Schiff base derivatives. • molecular docking and ADMET properties of the synthesised compounds. The search for novel antidiabetic agents remains a major focus in pharmaceutical research, particularly those targeting carbohydrate-hydrolysing enzymes such as α-glucosidase. In this study, a series of novel 4-amino-2H-1,2,4-triazol-3(4H)-one (1) and its Schiff base derivatives (2–10) were synthesised via two steps. Firstly, carbonohydrazide was reacted with triethyl orthoformate via a modified Boulton–Katritzky reaction, followed by Schiff base formation with various substituted aldehydes. Structures of synthesised compounds was confirmed using 1 H-NMR and EI-MS spectroscopic techniques. The inhibitory activities of the compounds against α-glucosidase were evaluated, alongside molecular docking studies and in silico ADMET profiling. Compounds 2, 3, 4, 5, and 10 exhibited good inhibitory activities with IC₅₀ values of 12.4 ± 0.43, 12.6 ± 0.33, 15.7 ± 0.11, 17.5 ± 0.36, and 11.95 ± 0.35 µM, respectively. Notably, compound 6 (4-(2,3,4-trimethoxybenzylideneamino)-2H-1,2,4-triazol-3(4H)-one), bearing a 2,3,4-trimethoxy substituent, showed the best potency with an IC₅₀ of 11.4 ± 0.56 µM, surpassing the standard, acarbose (IC₅₀ = 23.0 ± 0.13 µM). Structure–activity relationship (SAR) revealed that polyhydroxylation and dense methoxy substitution enhanced inhibitory potency, whereas bulky or electron-withdrawing groups diminished activity. Molecular docking studies showed strong binding affinities for compounds 4 and 5, with values of −8.1 kcal/mol (10BB), −9.4 kcal/mol (8HDH), and −9.8 kcal/mol (8HDH), comparable to acarbose (−8.8 kcal/mol) and empagliflozin (−12.2 kcal/mol). ADMET analysis indicated that most compounds satisfied Lipinski’s and Pfizer’s rules, with compound 6 emerging as a promising lead.