New indole based hybrid oxadiazole scaffolds with N-substituted acetamides: As potent anti-diabetic agents

• Published in: Bioorganic chemistry 2018-12, Vol.81, p.253-263
• Main Authors: Nazir, Majid, Abbasi, Muhammad Athar, Aziz-ur-Rehman, Siddiqui, Sabahat Zahra, Khan, Khalid Mohammed, Kanwal, Salar, Uzma, Shahid, Muhammad, Ashraf, Muhammad, Arif Lodhi, Muhammad, Ali Khan, Farman
• Format: Article
• Language: English
• Subjects: Cytotoxicity; Indole; Inhibitors; Molecular docking; Oxadiazole; α-glucosidase
• ISSN: 0045-2068; 1090-2120
• DOI: 10.1016/j.bioorg.2018.08.010

[Display omitted] •Synthesis of new indole based hybrid oxadiazole scaffolds with N-substituted acetamides by multiple chemical transformations.•Structural characterization of compounds by various spectroscopic techniques.•Evaluation of compounds 8a-8l for in vitro α-glucosidase inhibitory activity.•Cytotoxicity evaluation of compounds 8a-8l by hemolytic activity.•Limited structure-activity relationship (SAR).•Assessment of ligand-enzyme binding interactions by in silico study. Current study is based on the sequential conversion of indolyl butanoic acid (1) into ethyl indolyl butanoate (2), indolyl butanohydrazide (3), and 1,3,4-oxadiazole-2-thiol analogs (4) by adopting chemical transformations. In a parallel series of reactions, 2-bromo-N-phenyl/arylacetamides (7a-l) were synthesized by reacting different amines derivatives (5a-l) with 2-bromoacetyl bromide (6) to serve as electrophile. Then, the synthesized electrophiles (7a-l) were treated with nucleophilic 1,3,4-oxadiazole-2-thiol analog (4) to afford a range of N-substituted derivatives (8a-l). The structural confirmation of all the synthetic compounds was carried out by IR, 1H-, 13C NMR, EI-MS, and CHN analysis data. All synthesized molecules (8a-l) were tested for their antidiabetic potential via inhibition of the α-glucosidase enzyme followed by their in silico study. Their cytotoxicity profile was also ascertained via hemolytic activity and all of them possessed very low cytotoxicity. Compounds 8h and 8l were found most active having IC50 values 9.46 ± 0.03 µM and 9.37 ± 0.03 µM, respectively. However, all other molecules also exhibited good to moderate inhibition potential with IC50 values between 12.68 ± 0.04–37.82 ± 0.07, compared to standard acarbose (IC50 = 37.38 ± 0.12 µM), hence can be used as lead molecules for further research in order to get better antidiabetic agents.