Synthetic access to syn-functionalised chiral hydroxy pyrrolidines and pyrrolidones: Evaluation of α-glucosidase inhibition activity, docking studies and pharmacokinetics prediction

• Published in: Bioorganic chemistry Vol. 129; p. 106115
• Main Authors: Mhaldar, Shashank N., Kotkar, Gayatri D., Tilve, Santosh G.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01-12-2022
• Subjects: Acarbose; alpha-Glucosidases - metabolism; Cross-aldol; Drug-likeness; Glycoside Hydrolase Inhibitors - pharmacology; Hydroxy pyrrolidines; Hydroxy pyrrolidones; Molecular docking; Molecular Docking Simulation; Molecular Structure; Organocatalysis; Pyrrolidines - pharmacology; Pyrrolidinones - pharmacology; Structure-Activity Relationship; α-Glucosidase inhibition; Drug-likeness; α-Glucosidase inhibition; Cross-aldol; Hydroxy pyrrolidones; Organocatalysis; Hydroxy pyrrolidines; Molecular docking
• ISSN: 0045-2068; 1090-2120
• DOI: 10.1016/j.bioorg.2022.106115

[Display omitted]
•New chiral hydroxy pyrrolidines and pyrrolidones are synthesized via cross aldol reaction.•The hydroxy pyrrolidines are more potent than pyrrolidones against α-glucosidase enzyme.•The polar hydroxy group and n-alkyl chain of pyrrolidines plays a significant role in inhibition.•In silico ADME/Toxicity shows that compounds have drug like properties and can be orally administered.•Compounds 9b and 9c showed promising results than the standard drugs in computational studies.
A new series of syn-functionalised chiral hydroxy pyrrolidines and pyrrolidones containing α,β-contiguous stereocenters were synthesized via a diphenylprolinol-catalysed asymmetric cross aldol reaction. The synthesized compounds were characterised and evaluated for their α-glucosidase inhibitory potential. The hydroxy pyrrolidine series (9a-9i) was found to be selectively more potent against the α-glucosidase enzyme as compared to the pyrrolidone series (10a-10i). Pyrrolidine 9b was the most efficacious analogue with an IC50 of 48.31 µM. Compounds 9c, 9d, &9f were also found to be more potent than the standard drugs acarbose, miglitol and deoxynojirimycin. Furthermore, these compounds were investigated by computational studies using the GLIDE docking module of the Schrödinger suite 2021-4 in which 9b and 9c showed more promising results than the standard drugs acarbose, miglitol, and deoxynojirimycin.