Synthetic thiosemicarbazones as a new class of Mycobacterium tuberculosis protein tyrosine phosphatase A inhibitors |
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Authors: | Larissa Sens Ana Caroline Arruda de Souza Lucas Antonio Pacheco Angela Camila Orbem Menegatti Mattia Mori Alessandra Mascarello Ricardo José Nunes Hernán Terenzi |
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Institution: | 1. Laboratório Estrutura e Atividade, Departamento de Química, LEAT-CFM-UFSC, Universidade Federal de Santa Catarina, Campus Trindade, 88040-900 Florianópolis, SC, Brazil;2. Centro de Biologia Molecular Estrutural, Departamento de Bioquímica, CEBIME-UFSC, Universidade Federal de Santa Catarina, Campus Trindade, 88040-900 Florianópolis, SC, Brazil;3. Department of Biotechnology, Chemistry and Pharmacy, University of Siena. Via Aldo Moro 2, 53100 Siena, Italy |
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Abstract: | Mycobacterium tuberculosis secretes two protein tyrosine phosphatases as virulence factors, PtpA and PtpB. Inhibition studies of these enzymes have shown significant attenuation of the M. tuberculosis growth in vivo. As PtpA mediates many effects on the regulation of host signaling ensuring the intracellular survival of the bacterium we report, for the first time, thiosemicarbazones as potential novel class of PtpA inhibitors. Several compounds were synthesized and biologically evaluated, revealing interesting results. Enzyme kinetic assays showed that compounds 5, 9 and 18 are non-competitive inhibitors of PtpA, with Ki values ranging from 1.2 to 5.6?µM. Modeling studies clarified the structure-activity relationships observed in vitro and indicated a possible allosteric binding site in PtpA structure. To the best of our knowledge, this is the first disclosure of potent non-competitive inhibitors of PtpA with great potential for future studies and development of analogues. |
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Keywords: | Tuberculosis PtpA Inhibitors Thiosemicarbazones |
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