Ullah_2024_Sci.Rep_14_7675

A serine protease called prolyl endopeptidase (PEP) hydrolyses the peptide bonds on the carboxy side of the proline ring. The excessive PEP expression in brain results in neurodegenerative illnesses like dementia, Alzheimer's disease, and Parkinson's disease. Results of the prior studies on antioxidant activity, and the non-cytotoxic effect of bi-carbazole-linked triazoles, encouraged us to extend our studies towards its anti-diabetic potential. Hence, for this purpose all compounds 1-9 were evaluated to reveal their anti-prolyl endo peptidase activity. Fortunately, seven compounds resulted into significant inhibitory capability ranging from 26 to 63 microM. Among them six compounds 4-9 exhibited more potent inhibitory activity with IC(50) values 46.10 +/- 1.16, 42.30 +/- 1.18, 37.14 +/- 1.21, 26.29 +/- 0.76, 28.31 +/- 0.64 and 31.11 +/- 0.84 microM respectively, while compound 3 was the least active compound in the series with IC(50) value 63.10 +/- 1.58 microM comparing with standard PEP inhibitor bacitracin (IC(50) = 125 +/- 1.50 microM). Moreover, mechanistic study was performed for the most active compounds 7 and 8 with K(i) values 24.10 +/- 0.0076 and 23.67 +/- 0.0084 microM respectively. Further, the in silico studies suggested that the compounds exhibited potential interactions and significant molecular conformations, thereby elucidating the structural basis for their inhibitory effects.