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Synthesis and antitubercular activity of new N-oxide compounds designed to treat multiresistant-tuberculosis

Grant number: 18/11079-0
Support type:Regular Research Grants
Duration: October 01, 2018 - December 31, 2020
Field of knowledge:Health Sciences - Pharmacy
Principal researcher:Jean Leandro dos Santos
Grantee:Jean Leandro dos Santos
Home Institution: Faculdade de Ciências Farmacêuticas (FCFAR). Universidade Estadual Paulista (UNESP). Campus de Araraquara. Araraquara , SP, Brazil
Assoc. researchers:Fernando Rogério Pavan


A few years ago the World Health Organization (WHO) established as one of the its goals the eradication of tuberculosis by the year 2015. Far from this aim, we reached the year 2016 within 10.4 million new cases of tuberculosis (TB) and 1.3 million deaths worldwide. The emergence of resistant strains is one of the factors that justify the difficulty of reaching the goal proposed by WHO. The increasing number of cases for multidrug resistant TB (MDR-TB) and extensively drug-resistant TB (XDR-TB) associated with high mortality rates, treatment's difficulties and high costs are current challenges. Bedaquiline is the only drug approved by the US Food and Drug Administration (FDA) for the treatment of MDR-TB and XDR-TB. However, resistant strains of this drug have already been characterized, justifying the need to discover new drugs. For more than 10 years, our research group has been looking to identify compounds with antituberculosis activity. By screening a library containing more than 5.000 molecules, we identified benzofuroxan derivatives with potent anti-TB activity against H37Rv strains and multidrug resistant clinical isolates with minimal inhibitory concentration (MIC 90) values ranging from 1.44 uM to 62 uM. Transcriptome studies have shown that the likely mechanism of action of these molecules is through the inhibition of protein synthesis. In this project, we propose the optimization of this benzofuroxane derivatives using the molecular modification strategy. The molecules will be synthesized, characterized and evaluated against strains of either Mycobacterium tuberculosis (MTB) H37Rv and multi-resistant clinical isolates (characterized phenotypically and genotypically). In addition, the determination of MIC90 intramacrophagical using murine macrophages J774A.1 and the ability of the compounds to inhibit the protein synthesis will be investigated. For the most active compound in vivo assay using infected murine will be performed in order to verify the proof of concept.This study is expected to identify new drug candidates for treatment of multidrug-resistant tuberculosis that may become an alternative to current anti-TB treatment. (AU)

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Scientific publications (7)
(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)
LOPES, JULIANA ROMANO; CHIBA, DIEGO EIDY; DOS SANTOS, JEAN LEANDRO. HIV latency reversal agents: A potential path for functional cure?. EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY, v. 213, MAR 5 2021. Web of Science Citations: 0.
FERNANDES, GUILHERME F. S.; CAMPOS, DEBORA L.; DA SILVA, ISABEL C.; PRATES, JOAO L. B.; PAVAN, ALINE R.; PAVAN, FERNANDO R.; DOS SANTOS, JEAN L. Benzofuroxan Derivatives as Potent Agents against Multidrug-Resistant Mycobacterium tuberculosis. CHEMMEDCHEM, v. 16, n. 8 FEB 2021. Web of Science Citations: 0.
DE FREITAS, NATALIA LOURENCO; DEBERALDINI, MARIA GABRIELA; GOMES, DIANA; PAVAN, ALINE RENATA; SOUSA, ANGELA; DOS SANTOS, JEAN LEANDRO; SOARES, CHRISTIANE P. Histone Deacetylase Inhibitors as Therapeutic Interventions on Cervical Cancer Induced by Human Papillomavirus. FRONTIERS IN CELL AND DEVELOPMENTAL BIOLOGY, v. 8, JAN 28 2021. Web of Science Citations: 0.
DE SOUZA, P. C.; FERNANDES, G. F. S.; MARINO, L. B.; RIBEIRO, C. M.; DA SILVA, P. B.; CHORILLI, M.; SILVA, C. S. P.; RESENDE, F. A.; SOLCIA, M. C.; DE GRANDIS, R. A.; COSTA, C. A. S.; CHO, S. H.; WANG, Y.; FRANZBLAU, S. G.; DOS SANTOS, J. L.; PAVAN, F. R. Furoxan derivatives demonstrated in vivo efficacy by reducing Mycobacterium tuberculosis to undetectable levels in a mouse model of infection. BIOMEDICINE & PHARMACOTHERAPY, v. 130, OCT 2020. Web of Science Citations: 0.
REIS, JULIANA SANTANA; CORREA, MARCOS ANTONIO; RIBEIRO, CLOVIS AUGUSTO; DOS SANTOS, JEAN LEANDRO. Synthesis and evaluation of 1,3,5-triazine derivatives as sunscreens useful to prevent skin cancer. Bioorganic & Medicinal Chemistry Letters, v. 29, n. 24 DEC 15 2019. Web of Science Citations: 0.
SANTOS FERNANDES, GUILHERME FELIPE; DENNY, WILLIAM ALEXANDER; DOS SANTOS, JEAN LEANDRO. Boron in drug design: Recent advances in the development of new therapeutic agents. EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY, v. 179, p. 791-804, OCT 1 2019. Web of Science Citations: 1.
DOS SANTOS FERNANDES, GUILHERME FELIPE; FERNANDES, BARBARA COLATTO; VALENTE, VALERIA; DOS SANTOS, JEAN LEANDRO. Recent advances in the discovery of small molecules targeting glioblastoma. EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY, v. 164, p. 8-26, FEB 15 2019. Web of Science Citations: 3.

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