Inhibition of Mycobacterium tuberculosis tyrosine phosphatase PtpA by synthetic chalcones: Kinetics, molecular modeling, toxicity and effect on growth

• Published in: Bioorganic & medicinal chemistry Vol. 18; no. 11; pp. 3783 - 3789
• Main Authors: Mascarello, Alessandra, Chiaradia, Louise Domeneghini, Vernal, Javier, Villarino, Andrea, Guido, Rafael V.C., Perizzolo, Paulo, Poirier, Valerie, Wong, Dennis, Martins, Priscila Graziela Alves, Nunes, Ricardo José, Yunes, Rosendo Augusto, Andricopulo, Adriano Defini, Av-Gay, Yossef, Terenzi, Hernán
• Format: Journal Article
• Language: English
• Published: Amsterdam Elsevier Ltd 01.06.2010; Elsevier
• Subjects: Antibacterial agents; Antibiotics. Antiinfectious agents. Antiparasitic agents; Antitubercular Agents - chemistry; Biological and medical sciences; Chalcones; Chalcones - chemical synthesis; Chalcones - chemistry; Chalcones - pharmacology; Kinetics; Medical sciences; Models, Molecular; Mycobacterium tuberculosis - drug effects; Mycobacterium tuberculosis - enzymology; Mycobacterium tuberculosis - growth & development; Pharmacology. Drug treatments; Protein Tyrosine Phosphatases - antagonists & inhibitors; Structure-Activity Relationship; Tuberculosis; Tyrosine phosphatase inhibitors; Chalcones; Tyrosine phosphatase inhibitors; Tuberculosis; Growth; Leukocyte; Toxicity; Phosphoric monoester hydrolases; Esterases; Flavonoid; Modeling; Molecular model; Bacteria; Antituberculous agent; Chemical synthesis; Enzyme; Naphthalene derivatives; In vitro; Biological activity; Mycobacterium tuberculosis; Mycobacteriales; Mycobacteriaceae; Hydrolases; Actinomycetes; Inhibitor; Kinetics; Antibacterial agent; Macrophage; Protein-tyrosine-phosphatase
• ISSN: 0968-0896; 1464-3391
• DOI: 10.1016/j.bmc.2010.04.051

We have recently identified five synthetic chalcones which inhibit the activity of Mycobacterium tuberculosis protein tyrosine phosphatase A (PtpA), an enzyme associated with M. tuberculosis infectivity, and we carried out the analysis of the molecular recognition of these inhibitors on their macromolecular target through Structure–Activity Relationship (SAR) studies and molecular modeling. Tuberculosis (TB) is a major cause of morbidity and mortality throughout the world, and it is estimated that one-third of the world’s population is infected with Mycobacterium tuberculosis. Among a series of tested compounds, we have recently identified five synthetic chalcones which inhibit the activity of M. tuberculosis protein tyrosine phosphatase A (PtpA), an enzyme associated with M. tuberculosis infectivity. Kinetic studies demonstrated that these compounds are reversible competitive inhibitors. In this work we also carried out the analysis of the molecular recognition of these inhibitors on their macromolecular target, PtpA, through molecular modeling. We observed that the predominant determinants responsible for the inhibitory activity of the chalcones are the positions of the two methoxyl groups at the A-ring, that establish hydrogen bonds with the amino acid residues Arg17, His49, and Thr12 in the active site of PtpA, and the substitution of the phenyl ring for a 2-naphthyl group as B-ring, that undergoes π stacking hydrophobic interaction with the Trp48 residue from PtpA. Interestingly, reduction of mycobacterial survival in human macrophages upon inhibitor treatment suggests their potential use as novel therapeutics. The biological activity, synthetic versatility, and low cost are clear advantages of this new class of potential tuberculostatic agents.