Asian Research Thesis Index

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.      viii   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.

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