Identification and further development of thiazolidinones spiro-fused to indolin-2-ones as potent and selective inhibitors of Mycobacterium tuberculosis protein tyrosine phosphatase B

• Published in: Tetrahedron Vol. 67; no. 35; pp. 6713 - 6729
• Main Authors: Vintonyak, Viktor V., Warburg, Karin, Over, Björn, Hübel, Katja, Rauh, Daniel, Waldmann, Herbert
• Format: Journal Article
• Language: English
• Published: OXFORD Elsevier Ltd 02.09.2011; Elsevier
• Subjects: Antibiotics. Antiinfectious agents. Antiparasitic agents; Bioactive; Biological and medical sciences; Chemical biology; Chemistry; Chemistry, Organic; Enzyme inhibitors; Exact sciences and technology; General aspects; Heterocyclic compounds; Heterocyclic compounds with n hetero atom and also o and/or s, se, te hetero atoms; Heterocyclic compounds with only one n hetero atom and condensed derivatives; Inhibitors; Medical sciences; Medicinal chemistry; Molecular modeling; Mortality; Mycobacterium tuberculosis; Organic chemistry; Panels; Pharmacology. Drug treatments; Physical Sciences; Preparations and properties; Proteins; Science & Technology; Separation; Tuberculosis; Tyrosine; Vaccinia virus; Chemical biology; Medicinal chemistry; Enzyme inhibitors; Molecular modeling; MPTPB; PTPB; IMPAIRS; BIOLOGY-ORIENTED SYNTHESIS; DISCOVERY; Nitro compound; Separation; Configuration; Nitrogen heterocycle; Isozyme; Phosphoprotein phosphatase; Phosphoric monoester hydrolases; Esterases; Selectivity; Mycobacterial infection; Organic halogen compounds; Racemic; Structure activity relation; Benzylic compound; Enantiomer; Force field method; Bacteria; Anilide; Human; Chordopoxvirinae; Enzyme; Orthopoxvirus; Solubility; Enzyme inhibitor; Biological activity; Spiran; Infection; Virus; Vaccinia virus; Antibiotic; Tuberculosis; Mycobacterium tuberculosis; Mycobacteriales; Poxviridae; Bacteriosis; Mycobacteriaceae; Hydrolases; Actinomycetes; Indole derivatives; Protein-tyrosine-phosphatase
• ISSN: 0040-4020; 1464-5416
• DOI: 10.1016/j.tet.2011.04.026

Tuberculosis continues to be a major cause of morbidity and mortality throughout the world. Protein tyrosine phosphatases from Mycobacterium tuberculosis are attractive targets for developing novel strategies in battling tuberculosis due to their role in the intracellular survival of M. tuberculosis in various infection models. Here, we report on the identification and further development of thiazolidinones spiro-fused to indolin-2-ones as a new class of potent and selective inhibitors of M. tuberculosis protein tyrosine phosphatase B. Detailed structure–activity relationship (SAR) studies revealed that a nitro-substituted 2-oxoindole core together with a dihalogenated anilide and a halogenated N-benzyl moiety are essential for strong inhibitory activity against MptpB ( M. tuberculosis protein tyrosine phosphatase B). Small structural modification of the identified compounds led to significant improvement of compound solubility and cell permeability retaining inhibitory activity in the micromolar range. The configuration of the spiro-center was found to be crucial for the inhibitory activity and the separation of the racemate revealed the R-(−)-enantiomers as the biologically active component. The reported MptpB inhibitors show excellent selectivity against a selected panel of protein tyrosine phosphatases, including MptpA ( M. tuberculosis protein tyrosine phosphatase A), PTP1B (protein tyrosine phosphatase 1B), SHP-2 (Src homology 2 domain-containing protein tyrosine phosphatase), PTPN2, h-PTPβ (human protein tyrosine phosphatase β), and VHR ( Vaccinia virus VH1-related dual-specific protein phosphatase) and further highlight the identified thiazolidinones spiro-fused to indolin-2-ones as a promising class of new compounds that might prove useful for chemical biology research to dissect MptpB function and eventually foster the development of next generation antibiotics. [Display omitted]