Design, Synthesis, and Characterization of N-Oxide-Containing Heterocycles with in Vivo Sterilizing Antitubercular Activity

Author(s):Show less -

dos Santos Fernandes, Guilherme Felipe ^{[1, 2, 3]} ; de Souza, Paula Carolina ^{[1, 4]} ; Moreno-Viguri, Elsa ^[2] ; Santivanez-Veliz, Mery ^[2] ; Paucar, Rocio ^[2] ; Perez-Silanes, Silvia ^[2] ; Chegaev, Konstantin ^[5] ; Guglielmo, Stefano ^[5] ; Lazzarato, Loretta ^[5] ; Fruttero, Roberta ^[5] ; Chin, Chung Man ^[1] ; da Silva, Patricia Bento ; Chorilli, Marlus ^[1] ; Solcia, Mariana Cristina ^[1] ; Ribeiro, Camila Maringolo ^[1] ; Paiva Silva, Caio Sander ^[1] ; Marino, Leonardo Biancolino ^[1] ; Bosquesi, Priscila Longhin ^[1] ; Hunt, Debbie M. ^[6] ; de Carvalho, Luiz Pedro S. ^[6] ; de Souza Costa, Carlos Alberto ^[7] ; Cho, Sang Hyun ^[4] ; Wang, Yuehong ^[4] ; Franzblau, Scott Gary ^[4] ; Pavan, Fernando Rogerio ^[1] ; dos Santos, Jean Leandro ^{[1, 3]}

Affiliation

^[1] Sao Paulo State Univ UNESP, Sch Pharmaceut Sci, BR-14800903 Araraquara - Brazil

^[2] Univ Navarra, Dept Organ & Pharmaceut Chem, Inst Salud Trop, Pamplona 31008 - Spain

^[3] Sao Paulo State Univ UNESP, Inst Chem, BR-14800060 Araraquara - Brazil

^[4] Univ Illinois, Inst TB Res, Chicago, IL 60607 - USA

^[5] Univ Turin, Dipartimento Sci & Tecnol Farm, I-10124 Turin - Italy

^[6] Francis Crick Inst, Mycobacterial Metab & Antibiot Res Lab, 1 Midland Rd, London NW1 1AT - England

^[7] Sao Paulo State Univ UNESP, Sch Odontol, BR-14801903 Araraquara - Brazil

• Document type: Journal article
• Source: Journal of Medicinal Chemistry; v. 60, n. 20, p. 8647-8660, OCT 26 2017.
• Web of Science Citations: 10

Abstract

Tuberculosis, caused by Mycobacterium tuberculosis (Mtb), is the infectious disease responsible for the highest number of deaths worldwide. Herein, 22 new N-oxide-containing compounds were synthesized followed by in vitro and in vivo evaluation of their antitubercular potential against Mtb. Compound 8 was found to be the most promising compound, with MIC(90)values of 1.10 and 6.62 mu M against active and nonreplicating Mtb, respectively. Additionally, we carried out in vivo experiments to confirm the safety and efficacy of compound 8; the compound was found to be orally bioavailable and highly effective, leading to a reduction of Mtb to undetectable levels in a mouse model of infection. Microarray-based initial studies on the mechanism of action suggest that compound 8 blocks translation. Altogether, these results indicate that benzofuroxan derivative 8 is a promising lead compound for the, development of a novel chemical class of antitubercular drugs. (AU)

• FAPESP's process: 15/19531-1 - Targeting histone deacetylase (HDAC-1 and HDAC-2) as mechanisms to induce fetal hemoglobin in sickle cell disease
• Grantee: Jean Leandro dos Santos
• Support Opportunities: Regular Research Grants
• FAPESP's process: 13/14957-5 - Research potential against tuberculosis of a new class of furoxan compounds and nanostructured compounds of the ruthenium(II) and copper (II)
• Grantee: Fernando Rogério Pavan
• Support Opportunities: Research Grants - Young Investigators Grants
• FAPESP's process: 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
• Grantee: Guilherme Felipe dos Santos Fernandes
• Support Opportunities: Scholarships abroad - Research Internship - Master's degree
• FAPESP's process: 14/11586-9 - Studies in vitro and in vivo of furoxan compounds with potential application for the treatment of tuberculosis
• Grantee: Paula Carolina de Souza
• Support Opportunities: Scholarships in Brazil - Doctorate
• FAPESP's process: 14/03920-6 - Evaluation of pharmacological interaction and bactericidal kinetics of new furoxanic molecules in combination with rifampicin, isoniazid, amikacin, and moxifloxacin against Mycobacterium tuberculosis H37Rv
• Grantee: Camila Maríngolo Ribeiro
• Support Opportunities: Scholarships in Brazil - Scientific Initiation
• 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: 16/02860-5 - In vitro and in vivo studies of furoxan compounds: permeability, frequency of resistance, activity against resistance strains and in vivo efficacy
• Grantee: Paula Carolina de Souza
• Support Opportunities: Scholarships abroad - Research Internship - Doctorate
• FAPESP's process: 14/02240-1 - Design, Synthesis and anti Mycobacterium tuberculosis activity of new N-oxides derivatives
• Grantee: Guilherme Felipe dos Santos Fernandes
• Support Opportunities: Scholarships in Brazil - Master