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

Abstract

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 pi 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.

Cinnamic Derivatives in Tuberculosis

“…The structure-activity analysis revealed that the predominant factor for the activity is the molecular planarity and/or hydrophobicity and the nature of the substituents. Later on, the molecular recognition of these inhibitors on PtpA was investigated through molecular modeling, these investigations revealing that the binding and the inhibitory activity of the chalcones are predominantly governed by the positions of the two methoxyl groups at the B-ring (Mascarello et al, 2010). Besides, theOMe groups proved to establish key hydrogen bonds with the amino acid residues Arg17, His49 and Thr12 in the active site of PtpA while the 2-naphthyl A-ring undergoes л-stacking interaction with the Trp48 residue.…”

Three closely related 1-(naphthalen-2-yl)prop-2-en-1-ones: pseudosymmetry, disorder and supramoleular assembly mediated by C—H...π and C—Br...π interactions

“…It has been observed that when electron-rich naphthyl rings are present in chalcones they can participate in -stacking interactions, and this can play an important role in orientating inhibitors within the active sites of enzymes (Mascarello et al, 2010), while chalcones containing heterocyclic substituents additionally exhibit fungistatic and fungicidal properties (Opletalová & Sedivý, 1999).…”

Interactions of Three Chalcones with Human Serum Albumin Revealed by Spectroscopic Techniques

“…15 Hesperidin methyl chalcones have vasoprotective activity and may cure acute hemorrhoid and chronic venous insufficiency. 16 Bombardelli et al 17 found that the chalcones derivatives, such as 2′,4′,4-triHC and 2′,4′-diHC, exhibited a significant affinity to estrogen receptors of type II, and a conspicuous anti-proliferative activity on ovary, uterus and breast tumor cell lines.…”