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.

Fig. 1. Design concept of the new the β-amino-N-acylhydrazone derivative (5) proposed as a DPP-4 inhibitor by molecular hybridisation between sitagliptin (1) and LASSBio-1773 (2).

Fig. 2. Selected variables considered in the study of the β-amino-N-acylhydrazone core.

Fig. 3. Superposition of compounds (6-R) (blue), (6-S) (orange) and sitagliptin (1-R) (green) inside DPP-4 active site.

Fig. 4. Superposition of compounds (6-R-E) (purple), (6-S-Z) (orange) and R-sitagliptin (1-R) (green) at the DPP-4 active site.

Fig. 5. Superposition of compounds (13-R) (green) and R-sitagliptin (1-R) (purple) inside DPP-4 active site.

Scheme 1. (A) Synthesis of compounds (5–7), (9), (13–14) as racemic mixtures. (B) Methodology for the chiral resolution of β-aminoester (20) and its application in the synthesis of the target compounds (6-R) and (6-S).

Fig. 6. (A) Conformers s-cis and s-trans of compound (7). (B) NOE correlations found for compound (14).

Fig. 7. Chemical stability of LASSBio-2123 (5), LASSBio-2124 (6) and LASSBio-2125 (7) (A) results at pH = 7.4. (B) Results at pH = 2.0. The experiments were conducted in triplicate, and the values shown represent the average of the experiments.

Fig. 8. Preliminary structure–activity relationships for LASSBio-2123 to LASSBio-2130 (5–7, 9, 13, 14, 6-R, 6-S) as DPP-4 inhibitors.