Synthesis and anti-Mycobacterium tuberculosis evaluation of new nitroimidazooxazine derivatives useful for the treatment of multidrug-resistant tuberculosis

• Grant number: 20/13279-7
• Support Opportunities: Regular Research Grants
• Start date: July 01, 2021
• End date: June 30, 2023
• Field of knowledge: Health Sciences - Pharmacy
• Principal Investigator: Jean Leandro dos Santos
• Grantee: Jean Leandro dos Santos
• Host Institution: Faculdade de Ciências Farmacêuticas (FCFAR). Universidade Estadual Paulista (UNESP). Campus de Araraquara. Araraquara , SP, Brazil
• Associated researchers: Chung Man Chin ; Fernando Rogério Pavan ; Javier Alcides Ellena ; William Alexander Denny

Abstract

Although advances have been made in recent years for the treatment of tuberculosis (TB), huge challenges such as the emergence of resistant strains become distant the goals to achieve the eliminating the disease in the near future. According to the World Health Organization (WHO), in 2018 about 10 million new cases were diagnosed and 1.2 million deaths occurred. Among the new cases, 484,000 patients had exhibited multidrug-resistant TB (MDR-TB) or extensively drug-resistant TB (XDR-TB), making treatment even more time-consuming and challenging. Over the past 11 years, intense efforts made by our research group have enabled, through a national and international research network, the discovery of new prototypes with potent anti-Mycobacterium tuberculosis (MTB) activity, including against MDR-TB and XDR-TB strains. Of these, the benzofuroxan derivative, known as BZ8 - protein synthesis inhibitor, reduced the colony-forming units in the animals' lungs to zero during the treatment of animals infected with the bacillus, an noteworthy effect not observed for any antitubercular drug currently available. Since then, structure-activity-relationship studies have allowed the identification of structural patterns necessary to maintain anti-MTB activity. In this project, we propose to obtain novel nitroimidazooxazine derivatives, designed through molecular modification approaches, as lead compounds active against MDR-TB and XDR-TB. All designed compounds will be synthesized and characterized by analytical methods. In addition, through phenotypic screening, nitroimidazooxazine derivatives will be evaluated against MTB H37Rv strains and MDR-TB and XDR-TB clinical isolates characterized phenotypically and genotypically. The intramacrophagic activity of MTB H37Rv in J774A.1 murine macrophages will also be investigated. Studies of spontaneous mutant isolation and resistance frequency will be conducted. In addition, to assess the mutagenicity and genotoxicity, it will be carried out in vitro and in vivo assays. It is expected in this study to identify new lead compounds that could be an alternative to the treatment of multidrug-resistant tuberculosis and / or that can improve the current treatment. (AU)

Scientific publications

(6)

(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)

PAVAN, ALINE RENATA; LOPES, JULIANA ROMANO; LIMA IMPERADOR, CARLOS HENRIQUE; CHIN, CHUNG MAN; DOS SANTOS, JEAN LEANDRO. Perspectives and challenges to discovering hemoglobin-inducing agents in Sickle Cell Disease. FRONTIERS IN MEDICINE, v. 9, p. 4-pg., 2022-09-08. (19/10746-6, 18/19523-7, 20/13279-7)

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)

RODRIGUEZ-SILVA, CRISTHIAN N.; PROKOPCZYK, IGOR MUCCILO; DOS SANTOS, JEAN LEANDRO. The Medicinal Chemistry of Chalcones as Anti-Mycobacterium tuberculosis Agents. MINI-REVIEWS IN MEDICINAL CHEMISTRY, v. 22, n. 16, p. 13-pg., 2022-01-01. (20/13279-7)

TERRONI, BARBARA; OLIVEIRA DE MORAES, LUIS HENRIQUE; PAVAN, ALINE RENATA; RODRIGUES, GERSON JHONATAN; DOS SANTOS, JEAN LEANDRO. Vascular Effects of the Fetal Hemoglobin Inducer Agent 3-(1,3-Dioxoisoindolin-2-yl) Benzyl Nitrate. PHARMACEUTICALS, v. 15, n. 11, p. 12-pg., 2022-11-01. (20/13279-7, 18/19523-7)

PAVAN, ALINE RENATA; LOPES, JULIANA ROMANO; DOS SANTOS, JEAN LEANDRO. The state of the art of fetal hemoglobin-inducing agents. EXPERT OPINION ON DRUG DISCOVERY, v. 17, n. 11, p. 15-pg., 2022-11-07. (18/19523-7, 21/10059-9, 20/13279-7, 15/19531-1, 10/12495-6, 12/50359-2, 15/21252-3)

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)