title: 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.
authors.affiliation: Centro de Biologia Molecular Estrutural, CEBIME-UFSC, Universidade Federal de Santa Catarina, Campus Trindade, 88040-900 Florianópolis-SC, Brasil.
authors.forename: Louise Domeneghini
authors.initials: LD
authors.lastname: Chiaradia
authors.forename: Priscila Graziela Alves
authors.initials: PG
authors.lastname: Martins
authors.forename: Marlon Norberto Sechini
authors.initials: MN
authors.lastname: Cordeiro
authors.forename: Rafael Victorio Carvalho
authors.initials: RV
authors.lastname: Guido
authors.forename: Gabriela
authors.initials: G
authors.lastname: Ecco
authors.forename: Adriano Defini
authors.initials: AD
authors.lastname: Andricopulo
authors.forename: Rosendo Augusto
authors.initials: RA
authors.lastname: Yunes
authors.forename: Javier
authors.initials: J
authors.lastname: Vernal
authors.forename: Ricardo José
authors.initials: RJ
authors.lastname: Nunes
authors.forename: Hernán
authors.initials: H
authors.lastname: Terenzi
mesh_terms: D000595:Amino Acid Sequence; D000995:Antitubercular Agents / Q000138:chemical synthesis* / Q000737:chemistry; D001426:Bacterial Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry; D001555:Benzene Derivatives / Q000138:chemical synthesis / Q000737:chemistry; D047188:Chalcones / Q000138:chemical synthesis* / Q000737:chemistry; D006801:Humans; D007700:Kinetics; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009169:Mycobacterium tuberculosis / Q000201:enzymology*; D009281:Naphthalenes / Q000138:chemical synthesis / Q000737:chemistry; D011485:Protein Binding; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1 / Q000037:antagonists & inhibitors / Q000737:chemistry; D017027:Protein Tyrosine Phosphatases / Q000037:antagonists & inhibitors* / Q000737:chemistry; D016415:Sequence Alignment; D013329:Structure-Activity Relationship
chemical_list: D000995:Antitubercular Agents; D001426:Bacterial Proteins; D001555:Benzene Derivatives; D047188:Chalcones; C414465:MptpA protein, Mycobacterium tuberculosis; D009281:Naphthalenes; C516607:PTPN1 protein, human; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1; D017027:Protein Tyrosine Phosphatases