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.
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