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

• Grant number: 16/09502-7
• Support Opportunities: 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 Investigator: Jean Leandro dos Santos
• Grantee: Guilherme Felipe dos Santos Fernandes
• Host 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.

Scientific publications

(13)

(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)

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; et al. Discovery of phenylsulfonylfuroxan derivatives as gamma globin inducers by histone acetylation. EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY, v. 154, p. 341-353, JUN 25 2018. (10/12495-6, 14/00984-3, 16/09502-7, 13/04244-1, 14/06755-6)

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. (16/09502-7)

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. (18/11079-0, 16/09502-7, 18/17739-2)

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.; et al. 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. (18/11079-0, 18/00163-0, 14/03920-6, 17/12419-7, 16/09502-7, 14/02240-1, 13/14957-5, 16/02860-5, 14/24811-0, 16/24633-0, 18/17739-2, 15/19531-1, 16/22429-7, 14/11586-9)

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. (18/00163-0, 18/17739-2, 18/21778-3, 18/24783-8, 18/11079-0, 16/09502-7)

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. (18/11079-0, 16/09502-7)

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. (14/02240-1, 16/09502-7)

FERNANDES, GUILHERME F. S.; MANIERI, KARYN F.; BONJORNO, ANDRESSA F.; CAMPOS, DEBORA L.; RIBEIRO, CAMILA M.; DEMARQUI, FERNANDA M.; RUIZ, DANIEL A. G.; NASCIMENTO-JUNIOR, NAILTON M.; DENNY, WILLIAM A.; THOMPSON, ANDREW M.; et al. Synthesis and Anti-Mycobacterium tuberculosis Activity of Imidazo[2,1-b][1,3]oxazine Derivatives against Multidrug-Resistant Strains. CHEMMEDCHEM, v. 18, n. 12, p. 10-pg., 2023-04-21. (18/00163-0, 18/00187-7, 20/08370-5, 20/13279-7, 18/17739-2, 16/09502-7, 21/14973-7, 20/13497-4)

FERREIRA DE MELO, THAIS REGINA; DULMOVITS, BRIAN M.; DOS SANTOS FERNANDES, GUILHERME FELIPE; DE SOUZA, CRISTIANE M.; LANARO, CAROLINA; HE, MINGHZU; AL ABED, YOUSEF; CHUNG, MAN CHIN; BLANC, LIONEL; COSTA, FERNANDO FERREIRA; et al. Synthesis and pharmacological evaluation of pomalidomide derivatives useful for sickle cell disease treatment. BIOORGANIC CHEMISTRY, v. 114, SEP 2021. (16/09502-7, 15/19531-1, 13/04244-1, 10/12495-6, 14/00984-3, 14/06755-6)

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; et al. 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. (15/19531-1, 13/14957-5, 14/24811-0, 14/11586-9, 14/03920-6, 16/09502-7, 16/02860-5, 14/02240-1)

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. (15/19531-1, 16/08470-4, 16/08880-8, 16/09502-7)

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. (15/21252-3, 16/09502-7, 15/19531-1)

FERNANDES, GUILHERME F. S.; THOMPSON, ANDREW M.; CASTAGNOLO, DANIELE; DENNY, WILLIAM A.; DOS SANTOS, JEAN L.. Tuberculosis Drug Discovery: Challenges and New Horizons. Journal of Medicinal Chemistry, v. 65, n. 11, p. 43-pg., 2022-06-09. (18/11079-0, 16/09502-7, 18/17739-2, 20/13279-7)

Academic Publications

(References retrieved automatically from State of São Paulo Research Institutions)

FERNANDES, Guilherme Felipe dos Santos. Design, synthesis and anti-Mycobacterium tuberculosis evaluation of new benzofuroxan and nitroimidazooxazine derivatives useful for the treatment of multiresistant tuberculosis. 2021. Doctoral Thesis - Universidade Estadual Paulista (Unesp). Instituto de Química. Araraquara Araraquara.