Synthesis, biological evaluation, and molecular modeling of chalcone derivatives as potent inhibitors of Mycobacterium tuberculosis protein tyrosine phosphatases (PtpA and PtpB)

Louise Domeneghini Chiaradia; Priscila Graziela Alves Martins; Marlon Norberto Sechini Cordeiro; Rafael Victorio Carvalho Guido; Gabriela Ecco; Adriano Defini Andricopulo; Rosendo Augusto Yunes; Javier Vernal; Ricardo José Nunes; Hernán Terenzi

doi:10.1021/jm2012062

Synthesis, biological evaluation, and molecular modeling of chalcone derivatives as potent inhibitors of Mycobacterium tuberculosis protein tyrosine phosphatases (PtpA and PtpB)

J Med Chem. 2012 Jan 12;55(1):390-402. doi: 10.1021/jm2012062. Epub 2011 Dec 20.

Authors

Louise Domeneghini Chiaradia¹, Priscila Graziela Alves Martins, Marlon Norberto Sechini Cordeiro, Rafael Victorio Carvalho Guido, Gabriela Ecco, Adriano Defini Andricopulo, Rosendo Augusto Yunes, Javier Vernal, Ricardo José Nunes, Hernán Terenzi

Affiliation

¹ Centro de Biologia Molecular Estrutural, CEBIME-UFSC, Universidade Federal de Santa Catarina, Campus Trindade, 88040-900 Florianópolis-SC, Brasil.

PMID: 22136336
DOI: 10.1021/jm2012062

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Amino Acid Sequence
Antitubercular Agents / chemical synthesis*
Antitubercular Agents / chemistry
Bacterial Proteins / antagonists & inhibitors*
Bacterial Proteins / chemistry
Benzene Derivatives / chemical synthesis
Benzene Derivatives / chemistry
Chalcones / chemical synthesis*
Chalcones / chemistry
Humans
Kinetics
Models, Molecular*
Molecular Sequence Data
Mycobacterium tuberculosis / enzymology*
Naphthalenes / chemical synthesis
Naphthalenes / chemistry
Protein Binding
Protein Tyrosine Phosphatase, Non-Receptor Type 1 / antagonists & inhibitors
Protein Tyrosine Phosphatase, Non-Receptor Type 1 / chemistry
Protein Tyrosine Phosphatases / antagonists & inhibitors*
Protein Tyrosine Phosphatases / chemistry
Sequence Alignment
Structure-Activity Relationship

Substances

Antitubercular Agents
Bacterial Proteins
Benzene Derivatives
Chalcones
MptpA protein, Mycobacterium tuberculosis
Naphthalenes
PTPN1 protein, human
Protein Tyrosine Phosphatase, Non-Receptor Type 1
Protein Tyrosine Phosphatases