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Design, synthesis and antitubercular activity of new oxazolidinones useful for the treatment of multidrug-resistant tuberculosis

Grant number: 16/09502-7
Support type:Scholarships in Brazil - Doctorate
Effective date (Start): December 01, 2016
Effective date (End): November 13, 2020
Field of knowledge:Health Sciences - Pharmacy - Medicines Analysis and Control
Principal researcher:Jean Leandro dos Santos
Grantee:Guilherme Felipe dos Santos Fernandes
Home Institution: Faculdade de Ciências Farmacêuticas (FCFAR). Universidade Estadual Paulista (UNESP). Campus de Araraquara. Araraquara , SP, Brazil
Associated scholarship(s):18/17739-2 - Synthesis of New Nitroimidazooxazine Derivatives Designed as Antitubercular Agents, BE.EP.DR

Abstract

Mycobacterium tuberculosis, the main agent of tuberculosis (TB), is responsible for the annual death of 1.5 million people worldwide. Currently, one of the major global concerns is the increasing number of cases of multi drug-resistant tuberculosis (MDR-TB) and extensively drug resistant tuberculosis (XDR-TB) due to the high mortality rate, difficulty of treatment and the high costs involved. Bedaquiline is the only therapeutic option approved by the North American agency Food and Drug Administration (FDA) for treatment of MDR-TB and XDR-TB, however, strains resistant to this drug has already been characterized justifying the need for the discovery of new drugs. Through a phenotypic screening from a library containing more than 5 thousand molecules, we have identified benzofuroxan derivatives with potent anti-TB activity against MTB H37Rv strain and multidrug-resistant clinical isolates, with MIC90 values ranging from 1.44 uM to 62 uM. Moreover, transcriptomic studies revealed that the probable mechanism of action of these compounds occurs through the inhibition of protein synthesis by binding the mycobacterial ribosome. Therefore, in order to optimize this class of compounds and using the molecular modification strategy, we will synthesise two novel series of hybrid compounds which will be evaluated against strains of MTB H37Rv and multidrug-resistant clinical isolates, phenotypically and genotypically characterized. Furthermore, it will also be investigated the likely mechanism and binding site in the ribosome of this new series of molecules through assays using mycobacteriophages and toeprinting. In the present study, it is expected identify new drug candidates for the treatment of multidrug-resistant tuberculosis that could become an alternative to the current anti-TB treatment.

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Scientific publications (9)
(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)
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.
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.
FERREIRA DE MELO, THAIS REGINA; KUMKHAEK, CHUTIMA; DOS SANTOS FERNANDES, GUILHERME FELIPE; LOPES PIRES, MARIA ELISA; CHELUCCI, RAFAEL CONSOLIN; BARBIERI, KARINA PEREIRA; COELHO, FERNANDA; DE OLIVEIRA CAPOTE, TICIANA SIDORENKO; LANARO, CAROLINA; CARLOS, IRACILDA ZEPPONE; MARCONDES, SISI; CHEGAEV, KONSTANTIN; GUGLIELMO, STEFANO; FRUTTERO, ROBERTA; CHUNG, MAN CHIN; COSTA, FERNANDO FERREIRA; RODGERS, GRIFFIN P.; DOS SANTOS, JEAN LEANDRO. Discovery of phenylsulfonylfuroxan derivatives as gamma globin inducers by histone acetylation. EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY, v. 154, p. 341-353, JUN 25 2018. Web of Science Citations: 1.
DOS SANTOS FERNANDES, GUILHERME FELIPE; PAVAN, ALINE RENATA; DOS SANTOS, JEAN LEANDRO. Heterocyclic N-oxides - A Promising Class of Agents against Tuberculosis, Malaria and Neglected Tropical Diseases. CURRENT PHARMACEUTICAL DESIGN, v. 24, n. 12, p. 1325-1340, 2018. Web of Science Citations: 2.
SANTOS FERNANDES, GUILHERME FELIPE; BERNARDES SILVA, GABRIEL DALIO; PAVAN, ALINE RENATA; CHIBA, DIEGO EIDY; CHIN, CHUNG MAN; DOS SANTOS, JEAN LEANDRO. Epigenetic Regulatory Mechanisms Induced by Resveratrol. NUTRIENTS, v. 9, n. 11 NOV 2017. Web of Science Citations: 19.
DOS SANTOS FERNANDES, GUILHERME FELIPE; DE SOUZA, PAULA CAROLINA; MORENO-VIGURI, ELSA; SANTIVANEZ-VELIZ, MERY; PAUCAR, ROCIO; PEREZ-SILANES, SILVIA; CHEGAEV, KONSTANTIN; GUGLIELMO, STEFANO; LAZZARATO, LORETTA; FRUTTERO, ROBERTA; CHIN, CHUNG MAN; DA SILVA, PATRICIA BENTO; CHORILLI, MARLUS; SOLCIA, MARIANA CRISTINA; RIBEIRO, CAMILA MARINGOLO; PAIVA SILVA, CAIO SANDER; MARINO, LEONARDO BIANCOLINO; BOSQUESI, PRISCILA LONGHIN; HUNT, DEBBIE M.; DE CARVALHO, LUIZ PEDRO S.; DE SOUZA COSTA, CARLOS ALBERTO; CHO, SANG HYUN; WANG, YUEHONG; FRANZBLAU, SCOTT GARY; PAVAN, FERNANDO ROGERIO; DOS SANTOS, JEAN LEANDRO. Design, Synthesis, and Characterization of N-Oxide-Containing Heterocycles with in Vivo Sterilizing Antitubercular Activity. Journal of Medicinal Chemistry, v. 60, n. 20, p. 8647-8660, OCT 26 2017. Web of Science Citations: 10.
DOS SANTOS FERNANDES, GUILHERME FELIPE; CHIN, CHUNG MAN; DOS SANTOS, JEAN LEANDRO. Advances in Drug Discovery of New Antitubercular Multidrug-Resistant Compounds. PHARMACEUTICALS, v. 10, n. 2 JUN 2017. Web of Science Citations: 10.
DOS SANTOS FERNANDES, GUILHERME FELIPE; SALGADO, HERIDA REGINA NUNES; DOS SANTOS, JEAN LEANDRO. Isoniazid: A Review of Characteristics, Properties and Analytical Methods. CRITICAL REVIEWS IN ANALYTICAL CHEMISTRY, v. 47, n. 4, p. 298-308, 2017. Web of Science Citations: 8.

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