Synthesis and Biological Evaluation of Heterocyclic Derivatives Via Knoevenagel Products

Abstract

A facile methodology was developed which involved multicomponent single pot reaction which yielded the synthesis of highly functionalized 5-arylidene barbiturates/thiobarbiturates (158a – 166a), (158b – 167b), tricyclic-heterocycle compounds (158c – 163c) (158d – 164d), pyrimido[4,5‐d][1,3]diazine (170a – 173b), (170b – 174b) and pyrido[2,3‐d]pyrimidine‐6‐carboximidate, (176 – 181) and in good yields (60-95%). The discovered novel methodology involved sequential multicomponent reactions; consisting of Knoevenagel reaction followed by Michael addition; moreover, the proposed mechanism is consistent with the stepwise methodology which also availed the same tricyclic heterocycle compounds (158c – 163c) and (158d – 164d). In-silico (α glucosidase inhibitory studies) and in-vitro biological evaluation was extensively performed for synthesized tricyclic and bicyclic heterocyclic compounds. Tricyclic heterocycle compounds (158c – 163c) and (158d – 164d) showed excellent interacting affinity with receptor protein (PDB ID: 3A47) which were further complemented and confirmed through in-vitro α-glucosidase inhibitory studies which were found to be comparable with standard acarbose. Whereas, 160c 160d, 162d and 171b exhibited IC50 value (111.8, 99.4, 108.7, 121.4 µmol/L) as compared to standard acarbose (135.6 µmol/L) making them excellent α-glucosidase inhibition candidates among the lot. Furthermore, all the freshly synthesized compounds were screened for in-vitro antibacterial, and antioxidant studies, which revealed that all these compounds show mild bacteriostatic properties at 200 µM concentration against 105 CFU/200 µL of three bacterial strains; Pseudomonas aeruginosa, Escherichia coli, and Staphylococcus aureus, while compounds (159d, 160d, 161d, 163c, 163d) are found more potent antioxidants than the standard ascorbic acid.

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The barbituric acid derivatives (158a-165a) are less toxic as compared to the thiobarbituric derivatives (158b- 165b). Cheminformatics and docking score also supported that arylidene barbiturates and their derivatives follow the Lipinski rule due to which they would be excellent candidates as antioxidant and α-glucosidase inhibitors.