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Mascarello A.,Laboratorio Estrutura e Atividade | Chiaradia L.D.,Laboratorio Estrutura e Atividade | Vernal J.,Federal University of Santa Catarina | Vernal J.,Federal University of Rio de Janeiro | And 13 more authors.
Bioorganic and Medicinal Chemistry

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. © 2010 Elsevier Ltd. All rights reserved. Source

Chiaradia L.D.,Federal University of Santa Catarina | Chiaradia L.D.,Laboratorio Estrutura e Atividade | Martins P.G.A.,Federal University of Santa Catarina | Cordeiro M.N.S.,Laboratorio Estrutura e Atividade | And 7 more authors.
Journal of Medicinal Chemistry

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. © 2011 American Chemical Society. Source

De Lima Pimenta A.,Laboratorio Of Antibioticos | Chiaradia-Delatorre L.D.,Laboratorio Estrutura e Atividade | Mascarello A.,Laboratorio Estrutura e Atividade | De Oliveira K.A.,Laboratorio Of Biologia Of Gliomas | And 7 more authors.
International Journal of Antimicrobial Agents

New unconventional approaches to the development of antimicrobial drugs must target inhibition of infection stages leading to host colonisation or virulence itself, rather than bacterial viability. Amongst the most promising unconventional targets for the development of new antimicrobial drugs is bacterial adherence and biofilm formation as well as their control system, the quorum-sensing (QS) system, a mechanism of communication used to co-ordinate bacterial activities. Here we describe the evaluation of synthetic organic compounds as bacterial biofilm inhibitors against a panel of clinically relevant Gram-positive and Gram-negative bacterial strains. This approach has successfully allowed the identification of five compounds (GEt, GHex, GOctad, G19 and C33) active not only against bacterial biofilms but also displaying potential to be used as antagonists and/or inhibitors of bacterial QS. © 2013 Elsevier B.V. and the International Society of Chemotherapy. Source

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