Analysis of in vitro and in vivo activity of nitroimidazole derivatives against Mycobacterium tuberculosis

• Grant number: 20/08370-5
• Support Opportunities: Scholarships in Brazil - Master
• Start date: June 01, 2021
• End date: February 28, 2022
• Field of knowledge: Biological Sciences - Microbiology - Applied Microbiology
• Principal Investigator: Fernando Rogério Pavan
• Grantee: Karyn Fernanda Manieri
• Host Institution: Faculdade de Ciências Farmacêuticas (FCFAR). Universidade Estadual Paulista (UNESP). Campus de Araraquara. Araraquara , SP, Brazil

Abstract

Tuberculosis (TB) is an infectious disease whose main etiological agent is Mycobacterium tuberculosis. According to the WHO, cases of death from TB exceed the cases of HIV in the world, about 1.3 million a year. This chronic disease is often asymptomatic, coming to manifest itself only many years after the individual has been infected, thus estimating that about 1/4 of the world population has TB in its asymptomatic form, called latently. TB has a long treatment, consisting of the use of concomitant antibiotics, such as rifampicin (RFP), ethambutol (ETH), pyrazinamide (PZA) and isoniazid (INH), each having a different mechanism of action to prevent the emergence of resistant strains antibiotics. Even so, there is still a serious problem regarding mycobacterial resistance, where for more than 50 years the success of research for new antibiotics has been hampered by the emergence of resistant, multidrug-resistant (MDR-TB) and even extensively resistant strains (DR-TB). Our group has been working for some time and has published some very promising works with benzofuroxan compounds. In this search, we found a leading compound, called BZ8 that obtained, among other promising activities, the ability to 100% inhibit lung infection in BALB/c models. However, BZ8 was not as active in vitro in resistant strains and its chemistry has an N-oxide structure that can be unstable. Pretomanide, formerly known as PA-824, is a compound of the nitroimidazole class, recently approved for use in resistant infections. Our proposal was to develop a hybrid compound between pretomanida and BZ8. The project in question aims to evaluate the activities of these hybrid compounds in vitro and in vivo, using strains of M. tuberculosis in different metabolic conditions, because as is known, the bacillus tends to persist even in hypoxia and intracellular conditions, as well as its toxicity in an alternative model. (AU)

Scientific publications

(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)

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)

Academic Publications

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

MANIERI, Karyn Fernanda. Análise da atividade in vitro e in vivo de derivados nitroimizadóis frente ao Mycobacterium tuberculosis. 2022. Master's Dissertation - Universidade Estadual Paulista (Unesp). Faculdade de Ciências Farmacêuticas. Araraquara Araraquara.