Issue 10, 2024

Stereochemical insights into β-amino-N-acylhydrazones and their impact on DPP-4 inhibition

Abstract

Dipeptidyl peptidase IV (DPP-4) is a key enzyme that regulates several important biological processes and it is better known to be targeted by gliptins as a modern validated approach for the management of type 2 diabetes mellitus (T2DM). However, new generations of DPP-4 inhibitors capable of controlling inflammatory processes associated with chronic complications of T2DM are still needed. In this scenario, we report here the design by molecular modelling of new β-amino-N-acylhydrazones, their racemic synthesis, chiral resolution, determination of physicochemical properties and their DPP4 inhibitory potency. Theoretical and experimental approaches allowed us to propose a preliminary SAR, as well as to identify LASSBio-2124 (6) as a new lead for DPP-4 inhibition, with good physicochemical properties, favourable eudismic ratio, scalable synthesis and anti-diabetes effect in a proof-of-concept model. These findings represent an interesting starting point for the development of a new generation of DPP-4 inhibitors, useful in the treatment of T2DM and comorbidities.

Graphical abstract: Stereochemical insights into β-amino-N-acylhydrazones and their impact on DPP-4 inhibition

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Article information

Article type
Paper
Submitted
17 Jan 2024
Accepted
17 Feb 2024
First published
22 Feb 2024
This article is Open Access
Creative Commons BY-NC license

RSC Adv., 2024,14, 6617-6626

Stereochemical insights into β-amino-N-acylhydrazones and their impact on DPP-4 inhibition

E. Reina, L. S. Franco, T. R. Carneiro, E. J. Barreiro and L. M. Lima, RSC Adv., 2024, 14, 6617 DOI: 10.1039/D4RA00450G

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