Indole-carbohydrazide linked phenoxy-1,2,3-triazole-N-phenylacetamide derivatives as potent [alpha]-glucosidase inhibitors: design, synthesis, in vitro [alpha]-glucosidase inhibition, and computational studies

• Published in: BMC chemistry 2023-06, Vol.17 (1)
• Main Authors: Emadi, Mehdi, Mosavizadeh-Marvest, Fahimeh, Asadipour, Ali, Pourshojaei, Yaghoub, Hosseini, Samanesadat, Mojtabavi, Somayeh, Faramarzi, Mohammad Ali, Larijani, Bagher, Mohammadi-Khanaposhtani, Maryam, Mahdavi, Mohammad
• Format: Article
• Language: English
• Subjects: Acetanilide; Analysis; Antipyretics; Force and energy; Triazoles; Type 2 diabetes
• ISSN: 2661-801X; 2661-801X
• DOI: 10.1186/s13065-023-00971-w

A new series of indole-carbohydrazide-phenoxy-1,2,3-triazole-N-phenylacetamide hybrids 11a-o was designed based on molecular hybridization of the active pharmacophores of the potent [alpha]-glucosidase inhibitors. These compounds were synthesized and evaluated against [alpha]-glucosidase. The 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 [alpha]-glucosidase in vitro and in silico. ADMET properties of the most potent compounds were also predicted. All new derivatives 11a-o (IC.sub.50 values = 6.31 [+ or -] 0.03-49.89 [+ or -] 0.09 [micro]M) are excellent [alpha]-glucosidase inhibitors in comparison to acarbose (IC.sub.50 value = 750.0 [+ or -] 10.0 [micro]M) 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)acetamide 11d with IC.sub.50 = 6.31 [micro]M against MCF-7 cells, was 118.8-times more potent than acarbose. This compound is an uncompetitive inhibitor against [alpha]-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 compound 11d can be an orally active compound. According to obtained data, compound 11d can be a valuable lead compound for further structural development and assessments to obtain effective and potent new [alpha]-glucosidase inhibitors.