Synthesis of arylated tetrahydrobenzo[H]quinoline-3-carbonitrile derivatives as potential hits for treatment of diabetes

Aim: Quinoline scaffolds are serving as the core structure for numerous antifungal, analgesic, antipyretic, anti-inflammatory drugs as well as have also been investigated for their potential antidiabetic properties. Though further exploration is required in this area as the current antidiabetic agents, such as acarbose, miglitol and voglibose, are associated with several adverse side effects. In this context, arylated tetrahydrobenzo[H]quinoline-3-carbonitrile derivatives were designed and evaluated as potential antidiabetic agents. Materials & methods: A one-pot multicomponent reaction of 6-methoxy-1-tetralone with ethyl cyanoacetate, ammonium acetate and varying aldehydes yielded a range of new arylated tetrahydrobenzo[h]quinoline-3-carbonitrile molecules 1-36. Results: Compounds 2-5, 12, 13, 19 and 32-34 showed excellent inhibition against α-amylase (IC50 = 3.42–15.14 μM) and α-glucosidase (IC50 = 0.65–9.23 μM) enzymes in comparison to the standard acarbose (IC50 = 14.35 μM). In addition, all compounds revealed significant to moderate DPPH radical scavenging activity (SC50 = 21.30–138.30 μM) compared with BHT (SC50 = 64.40 μM). Kinetic studies confirmed competitive inhibition mode, while molecular docking studies comprehend ligands’ interaction with enzyme’s active sites and absorption, distribution, metabolism, and excretion analysis confirms that all synthetic derivatives are nontoxic. Conclusion: This research offers a range of lead candidates to become antidiabetic agents after further advanced study. A one-pot multicomponent reaction of 6-methoxy-1-tetralone with ethyl cyanoacetate, ammonium acetate, and varying aldehydes yielded a range of new arylated tetrahydrobenzo[h]quinoline-3-carbonitrile molecules 1-36. Structures of molecules were illustrated with the help of EI-MS, HREI-MS, 1H and 13C NMR spectroscopy. The inhibitory potential of all synthesized compounds was assessed against carbohydrate digestive enzymes, i.e., α-amylase and α-glucosidase, and evaluated for their capacity to scavenge DPPH radicals. Compounds 2-5, 12, 13, 19 and 32-34 showed excellent inhibition against α-amylase (IC50 = 3.42–15.14 μM) and α-glucosidase (IC50 = 0.65–9.23 μM) enzymes, on comparing with the standard acarbose (IC50 = 14.35 ± 0.13 μM). In addition, all compounds revealed significant to moderate DPPH radical scavenging activity (SC50 = 21.30–138.30 μM) compared with BHT (SC50 = 64.40 ± 0.19 μM). Structure–activity relationship analysis portrayed that compounds bearing nitro group at the aryl part were recognized as the most effective inhibitors against both enzymes. Kinetic studies on the active compounds were carried out, and the competitive mode of inhibition was confirmed. Furthermore, a molecular docking study was also conducted to comprehend ligands' interaction with the active site of the enzymes. According to the absorption, distribution, metabolism, and excretion analysis, all the synthetic derivatives are non-toxic.