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In the present study, we have designed a series of novel 1,2,3-triazole-aurone hybrids, which were synthesized by a one-pot click reaction between a terminal alkyne and an in-situ generated azide, and evaluated as potential cathepsin B inhibitors. The structures of the synthesized compounds were confirmed by various spectroscopic techniques (1H & 13C NMR and HRMS data). The in-vitro cathepsin B inhibitory study of the synthesized compounds showed that the hybrids named 3o, 3p, and 3r are the excellent inhibitors with percentage inhibition of 83.05–87.16% at the concentration of 10−5 ​M, in comparison to standards, Aspirin (48.21% at 10−7 ​M), and Curcumin (52.27% at 10−7 ​M). The docking study was also in support of the in-vitro assay. Furthermore, the anti-proliferative impact of these synthesized compounds was also evaluated against the gastric adenocarcinoma cell line (AGS cell line). The in-vitro MTT assay suggested that out of all the synthesized hybrids, compounds 3a with an IC50 value of 16 ​μM and 3b with an IC50 value of 11 ​μM possessed maximum cytotoxic activity against the AGS cell line in comparison to the reference, Oxaliplatin (IC50 ​= ​29 ​μM).

Cathepsin B represents a group of lysosomal-encapsulated cellular cysteine proteases, whose upregulation is the critical risk factor for cancer progression and in the regulation of degenerative processes like apoptosis. Therefore, cysteine cathepsins are used as effective biomarkers for cancers and other neurodegenerative disorders and have become specific targets in drug designing. To diversify the pharmacological potential of aurones, a total of eighteen novel 1,2,3-triazole decorated aurone hybrids were synthesized in very good yields, utilizing click chemistry and an ultrasound-assisted one-pot, multicomponent and greener protocol, straight from hydroxy-substituted aurones. These hybrids have been evaluated as useful cathepsin B inhibitors and further explored their in-vitro study over AGS cell line using MTT assay. The in-vitro cathepsin B inhibitory potential of the synthesized hybrids revealed that the hybrid 3p possesses a very significant inhibition (% inhibition ​= ​85.02) at the concentration of 10−6 M compared to the standard aspirin (% inhibition ​= ​48.21 ​at 10−7 M) and curcumin (% inhibition ​= ​57.72 ​at 10−7 M), which further supported by the in-silico studies. In addition to this, the cytotoxic assay of the hybrids showed that the hybrids 3d (IC50 ​= ​24 ​μM), 3i (IC50 ≈ 24 ​μM), and 3m (IC50 ​= ​26 ​μM) exhibit comparable anti-tumor activity against AGS cell line than the standard, oxaliplatin (IC50 ​= ​29 ​μM). The results suggested that the reported novel aurone-1,2,3-triazole hybrids are a promising candidate for the development of new cathepsin B inhibitors as well as anti-cancer leads.