Synthesis and Anti-Mycobacterium tuberculosis Activity of Imidazo[2,1-b][1,3]oxazine Derivatives against Multidrug-Resistant Strains

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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. ; Pavan, Fernando R. ; Dos Santos, Jean L.

• Document type: Journal article
• Source: CHEMMEDCHEM; v. 18, n. 12, p. 10-pg., 2023-04-21.

Abstract

The emergence of multidrug-resistant strains of M. tuberculosis has raised concerns due to the greater difficulties in patient treatment and higher mortality rates. Herein, we revisited the 2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine scaffold and identified potent new carbamate derivatives having MIC90 values of 0.18-1.63 mu M against Mtb H37Rv. Compounds 47-49, 51-53, and 55 exhibited remarkable activity against a panel of clinical isolates, displaying MIC90 values below 0.5 mu M. In Mtb-infected macrophages, several compounds demonstrated a 1-log greater reduction in mycobacterial burden than rifampicin and pretomanid. The compounds tested did not exhibit significant cytotoxicity against three cell lines or any toxicity to Galleria mellonella. Furthermore, the imidazo[2,1-b][1,3]oxazine derivatives did not show substantial activity against other bacteria or fungi. Finally, molecular docking studies revealed that the new compounds could interact with the deazaflavin-dependent nitroreductase (Ddn) in a similar manner to pretomanid. Collectively, our findings highlight the chemical universe of imidazo[2,1-b][1,3]oxazines and their promising potential against MDR-TB. (AU)

• FAPESP's process: 18/00163-0 - Development and search of new antimicrobials against Tuberculosis: from screening to pre-clinical studies in vivo
• Grantee: Fernando Rogério Pavan
• Support Opportunities: Regular Research Grants
• FAPESP's process: 18/00187-7 - Design, computational studies, synthesis and pharmacological evaluation of novel bioactive substances against nicotinic acetylcholine receptors alpha7 and alpha4beta2
• Grantee: Nailton Monteiro Do Nascimento Júnior
• Support Opportunities: Regular Research Grants
• FAPESP's process: 20/08370-5 - Analysis of in vitro and in vivo activity of nitroimidazole derivatives against Mycobacterium tuberculosis
• Grantee: Karyn Fernanda Manieri
• Support Opportunities: Scholarships in Brazil - Master
• FAPESP's process: 20/13279-7 - Synthesis and anti-Mycobacterium tuberculosis evaluation of new nitroimidazooxazine derivatives useful for the treatment of multidrug-resistant tuberculosis
• Grantee: Jean Leandro dos Santos
• Support Opportunities: Regular Research Grants
• FAPESP's process: 18/17739-2 - Synthesis of New Nitroimidazooxazine Derivatives Designed as Antitubercular Agents
• Grantee: Guilherme Felipe dos Santos Fernandes
• Support Opportunities: Scholarships abroad - Research Internship - Doctorate
• FAPESP's process: 16/09502-7 - Design, synthesis and antitubercular activity of new oxazolidinones useful for the treatment of multidrug-resistant tuberculosis
• Grantee: Guilherme Felipe dos Santos Fernandes
• Support Opportunities: Scholarships in Brazil - Doctorate
• FAPESP's process: 21/14973-7 - Synthesis and evaluation of new nitroimidazooxazine derivatives designed to act against drug-resistant Mycobacterium tuberculosis
• Grantee: Andressa Francielli Bonjorno
• Support Opportunities: Scholarships in Brazil - Master
• FAPESP's process: 20/13497-4 - Search for the mechanism of action and therapeutic effect of new classes of drugs against Mycobacterium tuberculosis
• Grantee: Fernando Rogério Pavan
• Support Opportunities: Regular Research Grants