Medicinal Chemistry Research https://doi.org/10.1007/s00044-020-02522-7 MEDICINAL CHEMISTR Y RESEARCH ORIGINAL RESEARCH New phthalimide-benzamide-1,2,3-triazole hybrids; design, synthesis, α-glucosidase inhibition assay, and docking study Seyed Esmaeil Sadat-Ebrahimi 1 ● Abbas Rahmani 1 ● Maryam Mohammadi-Khanaposhtani 2 ● Negar jafari 3 ● Somayeh Mojtabavi 4 ● Mohammad Ali Faramarzi 4 ● Mehdi Emadi 5 ● Azadeh Yahya-Meymandi 6 ● Bagher Larijani 7 ● Mahmoud Biglar 7 ● Mohammad Mahdavi 7 Received: 9 January 2020 / Accepted: 11 February 2020 © Springer Science+Business Media, LLC, part of Springer Nature 2020 Abstract A new series of phthalimide-benzamide-1,2,3-triazole hybrids 8a–k as α-glucosidase inhibitors was designed and synthesized. The biological evaluation of compounds 8a–k against yeast α-glucosidase demonstrated that all they have excellent inhibitory activity in comparison with standard inhibitor acarbose. Among them, the most potent compound was compound 8d with inhibitory activity 18.5-fold more than acarbose. Kinetic study revealed that α-glucosidase inhibition of compound 8d was the competitive type. Furthermore, docking study suggested that compound 8d is more stable than acarbose in the active site of α-glucosidase. Keywords Phthalimide ● Benzamide ● 1,2,3-Triazole ● Hybrid ● α-Glucosidase Introduction α-Glucosidase is a hydrolyzing enzyme that found in the brush border surface of intestine. The main function of this enzyme is conversion of carbohydrates (polysaccharides and disaccharides) into absorbable monosaccharide glucose (Chiba 1997). Therefore, this enzyme is involved in carbohydrate-related diseases such as diabetes, cancer, viral infections, and pompe disease (Toeller 1994; Pili et al. 1995; Howe et al. 2013; Shimada et al. 2014). In terms of prevalence, the most important carbohydrate-related disease is type 2 diabetes and some of sugar-containing α-glucosi- dase inhibitors, such as acarbose, miglitol, and voglibose are successfully used in the treatment of this disease (Fig. 1) (Van De Laar et al. 2005). However, these inhibitors were prepared by tedious multistep reactions and their clinical use is associated with gastrointestinal side effects (Hol- lander 1992). Thus, the discovery of effective small mole- cules with convenient synthesis, high inhibitory activity against α-glucosidase, and low side effects is an attractive target for pharmaceutical scientists (Taha et al. 2020; Rafique et al. 2019; Rahim et al 2020; Taha et al. 2015; Khan et al. 2014). Phthalimide is a fused heterocyclic structure that formed by the merger of benzene and pyrrole-2,5-dione. This scaffold was used as an important block in the design biological active compounds with properties such as anti-inflammatory, * Mahmoud Biglar mbiglar@tums.ac.ir * Mohammad Mahdavi momahdavi@tums.ac.ir 1 Department of Medicinal Chemistry, Faculty of Pharmacy and Pharmaceutical Sciences Research Center, Tehran University of Medical Sciences, Tehran, Iran 2 Cellular and Molecular Biology Research Center, Health Research Institute, Babol University of Medical Sciences, Babol, Iran 3 Department of Pharmaceutical Chemistry٫ Faculty of pharmacy, University of Kansas, Lawrence, KS 66045, USA 4 Department of Pharmaceutical Biotechnology, Faculty of Pharmacy and Biotechnology Research Center, Tehran University of Medical Sciences, Tehran, Iran 5 Electrical and Computer Engineering Department, Babol Noshirvani University of Technology, Babol, Iran 6 Department of Chemistry, Faculty of Science, University of Birjand, Birjand, Iran 7 Endocrinology and Metabolism Research Center, Endocrinology and Metabolism Clinical Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran Supplementary information The online version of this article (https:// doi.org/10.1007/s00044-020-02522-7) contains supplementary material, which is available to authorized users. 1234567890();,: 1234567890();,: