Urwa Khalid, Noor Fatima, Saeed Ullah, Sobia Ahsan Halim, Ajmal Khan*, Suraj N. Mali, Attalla F. El-kott, Mohammed A. AlShehri, Hamdy Kashtoh, Ahmed Al-Harrasi and Zahid Shafiq Pages 1 - 17 ( 17 )
Introduction: Prolyl oligopeptidase (POP) is a pivotal druggable target implicated in diverse biological processes and linked to the development of various ailments, including neurodegenerative disorders. While conventional peptide-based inhibitors have been a centerpiece, their limitations, such as restricted bioavailability, necessitate exploration of non-peptidic inhibitors for their therapeutic potential.
Method: This study focuses on designing, synthesizing, and assessing morpholine-based hydrazones targeting the catalytic serine residue of POP. The hydrazones (5a-o), reported as moderately potent analogs compared to the renowned Z-Pro-Prolinal, demonstrated in vitro POP inhibition with IC50 values ranging from 13.60 ± 2.51 to 36.51 ± 1.82 μM. The derivative 5h, with an IC50 of 13.60 ± 2.51 μM, emerged as the most potent inhibitor. Results: Moreover, the in vitro kinetic study of compound 5h indicated that it exhibited concentration-dependent type of inhibition. in silico docking studies of 5h revealed robust interactions in the POP enzyme's active site, yielding a docking score of ˗6.30 Kcal/- mol, consistent with experimental results. Conclusion: All findings underscored the potential of synthesized derivatives for drug development.Prolyl oligopeptidase (POP), prolyl endopeptidase (PEP), hydrazones, morpholine, molecular docking.