A Computer‐Driven Scaffold‐Hopping Approach Generating New PTP1B Inhibitors from the Pyrrolo[1,2‐a]quinoxaline Core

Abstract

Protein tyrosine phosphatase 1B (PTP1B) is a very promising target for the treatment of metabolic disorders such as type II diabetes mellitus. Although it was validated as a promising target for this disease more than 30 years ago, as yet there is no drug in advanced clinical trials, and its biochemical mechanism and functions are still being studied. In the present study, based on our experience generating PTP1B inhibitors, we have developed and implemented a scaffold‐hopping approach to vary the pyrrole ring of the pyrrolo[1,2‐a]quinoxaline core, supported by extensive computational techniques aimed to explain the molecular interaction with PTP1B. Using a combination of docking, molecular dynamics and end‐point free‐energy calculations, we have rationally designed a hypothesis for new PTP1B inhibitors, supporting their recognition mechanism at a molecular level. After the design phase, we were able to easily synthesize proposed candidates and their evaluation against PTP1B was found to be in good concordance with our predictions. Moreover, the best candidates exhibited glucose uptake increments in cellulo model, thus confirming their utility for PTP1B inhibition and validating this approach for inhibitors design and molecules thus obtained.

A comprehensive review on the research progress of PTP1B inhibitors as antidiabetics

“…Compound 52 , which had the best IC 50 value of 0.46 ± 0.04 μM, only raised glucose by 15% compared to control cells, while compound 53 (IC 50 = 0.79 ± 0.01 μM) showed a 30% rise. The most effective candidates also showed an increase in glucose absorption demonstrating their potential for PTP1B inhibition (García‐Marín et al, 2021). The structures of quinoxaline derivatives displaying potent PTP1B inhibitory activity are shown in Figure 16.…”

Computational Methods in Cooperation with Experimental Approaches to Design Protein Tyrosine Phosphatase 1B Inhibitors in Type 2 Diabetes Drug Design: A Review of the Achievements of This Century

“…Additionally, selectivity evaluation of these compounds against TCPTP showed that the most selective was compound 2 (two times, inhibitory activity on TCPTP: 44% at 1 µM). This molecule also increased glucose uptake by 15% relative to control cells in phenotypic models [109]. Ma and colleagues discovered imidazolidine-2,4-dione derivatives as PTP1B inhibitors with structural diver- In 2021, the scaffold-hopping approach was employed to optimize the structure of compound 1 based on the replacement of the pyrrole ring by azoles.…”

Synthesis of a Series of Quinoxaline Derivatives and Their Antibacterial Effectiveness Against Pathogenic Bacteria

“…These nitrogen‐based heterocyclic derivatives are known for their natural occurrence, remarkable drug‐like characteristics, and relative ease of synthesis [1–3] . They have been extensively studied and have shown potential as as analgesics, [4,5] anticancer agents, [6,7] antiviral agents, [8,9] antimicrobial agents, [10,11] anticonvulsants [12,13] and antidiabetics [14,15] . Moreover, quinoxaline derivatives have been used as synthetic antibiotics, exemplified by echinomycin and triostin A, which have demonstrated their efficacy against Gram‐positive bacteria.…”

“…[1][2][3] They have been extensively studied and have shown potential as as analgesics, [4,5] anticancer agents, [6,7] antiviral agents, [8,9] antimicrobial agents, [10,11] anticonvulsants [12,13] and antidiabetics. [14,15] Moreover, quinoxaline derivatives have been used as synthetic antibiotics, exemplified by echinomycin and triostin A, which have demonstrated their efficacy against Gram-positive bacteria. The broad spectrum of pharmaceutical functions and the success of quinoxaline antibiotics emphasize the importance of further investigating the potential of quinoxaline derivatives in antibacterial research.…”