Design and synthesis of new 1,4-di-N-oxide quinoxaline as antitubercular compounds to treat multi drug-resistant (MDR) and latent tuberculosis

• Grant number: 14/24811-0
• Support type: Scholarships abroad - Research Internship - Master's degree
• Effective date (Start): April 01, 2015
• Effective date (End): June 30, 2015
• Field of knowledge: Health Sciences - Pharmacy - Medicines Analysis and Control
• Principal researcher: Jean Leandro dos Santos
• Grantee: Guilherme Felipe dos Santos Fernandes
• Supervisor abroad: Silvia Perez
• Home Institution: Faculdade de Ciências Farmacêuticas (FCFAR). Universidade Estadual Paulista (UNESP). Campus de Araraquara. Araraquara , SP, Brazil
• Research place: Universidad de Navarra, Spain
• Associated to the scholarship: 14/02240-1 - Design, Synthesis and anti Mycobacterium tuberculosis activity of new N-oxides derivatives, BP.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 damages of about 12 billion dollars by year. 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. Compounds containing the N-oxide function such as quinoxalines has been described as prototypes for discovery of novel anti-TB drugs. The quinoxaline 1,4-di-N-oxide are heterocyclic compounds bioreducible and selectively toxic in hypoxic conditions, able to increase oxidative stress by increasing levels of reactive oxygen and nitrogen species and thus cause damage to the invading microorganisms. This class has been described as useful in treating not only the MDR-TB and XDR-TB, but also latent TB. In this context, we will synthesize and characterize the chemical structure of a series of quinoxalines designed by molecular hybridization strategy. These novel compounds will be further evaluated against MTB using H37Rv strains and MDR clinical isolates (genotypically and phenotypically characterized) by the laboratory of mycobacteria from School of Pharmaceutical Sciences, São Paulo State University - Araraquara -SP. (AU)

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)

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.

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.