BackgroundA new series of indole-carbohydrazide-phenoxy-1,2,3-triazole-N-phenylacetamide hybrids11a–owas designed based on molecular hybridization of the active pharmacophores of the potent α-glucosidase inhibitors. These compounds were synthesized and evaluated against α-glucosidase.MethodsThe 15 various derivatives of indole-carbohydrazide-phenoxy-1,2,3-triazole-N-phenylacetamide scaffold were synthesized, purified, and fully characterized. These derivatives were evaluated against yeast α-glucosidase in vitro and in silico. ADMET properties of the most potent compounds were also predicted.ResultsAll new derivatives11a–o(IC50values = 6.31 ± 0.03–49.89 ± 0.09 µM) are excellent α-glucosidase inhibitors in comparison to acarbose (IC50value = 750.0 ± 10.0 µM) that was used as a positive control. Representatively, (E)-2-(4-((4-((2-(1H-indole-2-carbonyl)hydrazono)methyl) phenoxy)methyl)-1H-1,2,3-triazol-1-yl)-N-(4-methoxyphenyl)acetamide11dwith IC50= 6.31 µM against MCF-7 cells, was 118.8-times more potent than acarbose. This compound is an uncompetitive inhibitor against α-glucosidase and showed the lowest binding energy at the active site of this enzyme in comparison to other potent compounds. Furthermore, computational calculations predicted that compound11dcan be an orally active compound.ConclusionAccording to obtained data, compound11dcan be a valuable lead compound for further structural development and assessments to obtain effective and potent new α-glucosidase inhibitors.Supplementary InformationThe online version contains supplementary material available at 10.1186/s13065-023-00971-w.