Synthesis, Biological Evaluation, And Molecular Modeling of Chalcone Derivatives As Potent Inhibitors of Mycobacterium tuberculosis Protein Tyrosine Phosphatases (PtpA and PtpB)

Abstract

Tuberculosis (TB) is a major infectious disease caused by Mycobacterium tuberculosis (Mtb). According to the World Health Organization (WHO), about 1.8 million people die from TB and 10 million new cases are recorded each year. Recently, a new series of naphthylchalcones has been identified as inhibitors of Mtb protein tyrosine phosphatases (PTPs). In this work, 100 chalcones were designed, synthesized, and investigated for their inhibitory properties against MtbPtps. Structure-activity relationships (SAR) were developed, leading to the discovery of new potent inhibitors with IC(50) values in the low-micromolar range. Kinetic studies revealed competitive inhibition and high selectivity toward the Mtb enzymes. Molecular modeling investigations were carried out with the aim of revealing the most relevant structural requirements underlying the binding affinity and selectivity of this series of inhibitors as potential anti-TB drugs.

Structure- and ligand-based drug design approaches for neglected tropical diseases

“…Several steps of the drug discovery process (e.g., hit identification, lead optimization, NCE discovery) can be improved in a rational way with the application of SBDD and LBDD methods [2,[7][8][9]. In this context, virtual screening has become a highly valued and widely used tool for the identification of hits and lead compounds for a variety of therapeutically important target proteins [2,[49][50][51][52].…”

“…In this context, the integration of modern drug discovery approaches allowing hit identification and lead optimization, as well as the discovery of innovative new chemical entities, are major challenges in this field [7][8][9][10][11]. The use of structure-(SBDD) and ligand-based drug design (LBDD) *Pure Appl.…”

“…It is worth noting that these knowledge-driven approaches can be explored in combination, creating new opportunities for innovation in medicinal chemistry in order to maximize the accomplishment of drug discovery projects. Recent successful examples highlight the diversity of SBDD and LBDD strategies, assembling the most powerful concepts in chemistry and biology, with particular emphasis on the field of NTDs [2,[7][8][9]. This paper outlines the fundamental principles and state of the art in the integration of SBDD and LBDD strategies for the discovery of innovative chemotherapy agents for a variety of NTDs, highlighting advances, limitations, and future perspectives in medicinal chemistry.…”

A fragment-based approach for the in silico prediction of blood-brain barrier permeation

“…The new paradigm of drug discovery involves a combination of classical and modern technologies with innovative strategies addressed to the design of new chemical entities (NCEs) with improved properties. [1][2][3] NCEs expected to advance into clinical trials should have a good balance of pharmacodynamic and pharmacokinetic properties. For the past decades, problems with absorption, distribution, metabolism and excretion (ADME) have been one of the major reasons for the failure of attractive compounds in advanced stages of drug development.…”

O 2 -Dependent Efficacy of Novel Piperidine- and Piperazine-Based Chalcones against the Human Parasite Giardia intestinalis

“…, antibacterial (27), antituberculosis (28), antifungal (29), anticancer (30), antileishmanial (31), anti-inflammatory (32), and even antigiardial (33) effects. A number of chalcone derivatives have also been found to inhibit several important enzymes in cellular systems, including protein tyrosinase (34), malarial aspartic acid protease, plasmepsin II (35), and malarial cysteine protease falcipain-2 (36).…”