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Design, Synthesis and anti Mycobacterium tuberculosis activity of new N-oxides derivatives

Grant number: 14/02240-1
Support type:Scholarships in Brazil - Master
Effective date (Start): June 01, 2014
Effective date (End): May 31, 2016
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):14/24811-0 - Design and synthesis of new 1,4-di-N-oxide quinoxaline as antitubercular compounds to treat multi drug-resistant (MDR) and latent tuberculosis, BE.EP.MS

Abstract

Mycobacterium tuberculosis ( MTB ), the main agent of tuberculosis ( TB ) , is responsible for the annual death of two to three million people worldwide, and global economic losses of about 12 billion dollars a year . Currently , one of the major global concerns is the increasing number of cases of multi - drug resistant ( MDR - TB ) and extensively drug resistant tuberculosis ( XDR - TB) due to the high mortality rate , difficulty of treatment and the high costs involved. It is estimated that , worldwide, the number of people infected with drug-resistant MTB first and second line people is 50 million. Currently , only the bedaquilina drug is approved by the North American agency - the Food and Drug Administration ( FDA ) - for treatment of MDR - TB and XDR - TB , a fact that justifies the need for the discovery of other agents to the therapeutic arsenal. Compounds containing the N-oxide function as furoxan and quinoxaline has been described as prototypes for discovery of new anti-TB drugs. Our research group previously identified furoxan compounds with activity against strains H37Rv and multi - drug resistant clinical isolates . These compounds showed minimum inhibitory concentration values of between 1.02 e 65.4 ¼M in resistant clinical isolates ( MDR - TB and XDR - TB ) and selectivity index between 10.4 and 105 . In addition, they were able to inhibit the activity of efflux pumps MTB, associated with drug resistance. Another class of compounds containing the N-oxide function is the quinoxaline 1,4- dioxide. These heterocyclic compounds , bioredutíveis in hypoxic conditions , are able to increase oxidative stress by increased levels of reactive oxygen species and nitrogen . This class has been described as useful in the treatment not only of MDR - TB and XDR - TB , but also in latent TB . In this context, we summarize and characterize the chemical structure of two series of compounds: furoxan (Series 1 ) and quinoxaline (Series 2 ) designed by molecular hybridization approach. These novel compounds will be further evaluated against MTB using strains H37Rv and MDR clinical isolates (genotypically and phenotypically characterized by the laboratory of mycobacteria FCF - UNESP Araraquara).

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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.
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; MORENO-VIGURI, ELSA; SANTIVANEZ-VELIZ, MERY; PAUCAR, ROCIO; CHIN, CHUNG MAN; PEREZ-SILANES, SILVIA; DOS SANTOS, JEAN LEANDRO. A Comparative Study of Conventional and Microwave-Assisted Synthesis of Quinoxaline 1,4-di-N-oxide N-acylhydrazones Derivatives Designed as Antitubercular Drug Candidates. Journal of Heterocyclic Chemistry, v. 54, n. 4, p. 2380-2388, JUL 2017. Web of Science Citations: 3.
GUILHERME FELIPE DOS SANTOS FERNANDES; CHUNG MAN CHIN; JEAN LEANDRO DOS SANTOS. POTENCIAIS ALVOS MOLECULARES PARA O DESENVOLVIMENTO DE NOVOS FÁRMACOS ANTITUBERCULOSE. Química Nova, v. 40, n. 5, p. -, Jun. 2017.
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.
DOS SANTOS FERNANDES, GUILHERME FELIPE; DE SOUZA, PAULA CAROLINA; MARINO, LEONARDO BIANCOLINO; CHEGAEV, KONSTANTIN; GUGLIELMO, STEFANO; LAZZARATO, LORETTA; FRUTTERO, ROBERTA; CHUNG, MAN CHIN; PAVAN, FERNANDO ROGERIO; DOS SANTOS, JEAN LEANDRO. Synthesis and biological activity of furoxan derivatives against Mycobacterium tuberculosis. EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY, v. 123, p. 523-531, NOV 10 2016. Web of Science Citations: 22.
PAVAN, ALINE RENATA; BERNARDES DA SILVA, GABRIEL DALIO; JORNADA, DANIELA HARTMANN; CHIBA, DIEGO EIDY; DOS SANTOS FERNANDES, GUILHERME FELIPE; CHIN, CHUNG MAN; DOS SANTOS, JEAN LEANDRO. Unraveling the Anticancer Effect of Curcumin and Resveratrol. NUTRIENTS, v. 8, n. 11 NOV 2016. Web of Science Citations: 33.
JORNADA, DANIELA HARTMANN; DOS SANTOS FERNANDES, GUILHERME FELIPE; CHIBA, DIEGO EIDY; FERREIRA DE MELO, THAIS REGINA; DOS SANTOS, JEAN LEANDRO; CHUNG, MAN CHIN. The Prodrug Approach: A Successful Tool for Improving Drug Solubility. Molecules, v. 21, n. 1 JAN 2016. Web of Science Citations: 29.
DOS SANTOS FERNANDES, GUILHERME FELIPE; JORNADA, DANIELA HARTMANN; DE SOUZA, PAULA CAROLINA; CHIN, CHUNG MAN; PAVAN, FERNANDO ROGERIO; DOS SANTOS, JEAN LEANDRO. Current Advances in Antitubercular Drug Discovery: Potent Prototypes and New Targets. Current Medicinal Chemistry, v. 22, n. 27, p. 3133-3161, 2015. Web of Science Citations: 7.

Please report errors in scientific publications list by writing to: cdi@fapesp.br.

Filed patent(s) as a result of this research project

COMPOSTOS DERIVADOS FUROXÂNICOS, COMPOSTOS DERIVADOS FUROXÂNICOS INTERMEDIÁRIOS, PROCESSOS DE OBTENÇÃO DOS MESMOS E SEUS USOS BR1020140315624 - Universidade Estadual Paulista (UNESP) . Jean Leandro dos Santos; Chung Man Ching; Fernando Rogério Pavan; Guilherme Felipe dos Santos Fernandes; Leonardo Biancolino Marino; Paula Carolina de Souza - December 2014, 17