esign, synthesis and biological evaluation of N-oxide derivatives with potent in vivo antileishmanial activit

Author(s)

Clementino, Leandro da Costa ^{[1, 2]} ; Santos Fernandes, Guilherme Felipe ^{[1, 2]} ; Prokopczyk, Igor Muccilo ^[2] ; Laurindo, Wilquer Castro ^{[1, 2]} ; Toyama, Danyelle ^[3] ; Motta, Bruno Pereira ^[2] ; Baviera, Amanda Martins ^[2] ; Henrique-Silva, Flavio ^[3] ; dos Santos, Jean Leandro ^[2] ; Graminha, Marcia A. S. ^[2]

Affiliation

^[1] Sao Paulo State Univ UNESP, Inst Chem, Araraquara, SP - Brazil

^[2] Sao Paulo State Univ UNESP, Sch Pharmaceut Sci, Araraquara, SP - Brazil

^[3] Univ Fed Sao Carlos, Dept Genet & Evolut, Sao Carlos - Brazil

• Document type: Journal article
• Source: PLoS One; v. 16, n. 11 NOV 1 2021.
• Web of Science Citations: 1

Abstract

Leishmaniasis is a neglected disease that affects 12 million people living mainly in developing countries. Herein, 24 new N-oxide-containing compounds were synthesized followed by in vitro and in vivo evaluation of their antileishmanial activity. Compound 4f, a furoxan derivative, was particularly remarkable in this regard, with EC50 value of 3.6 mu M against L. infantum amastigote forms and CC50 value superior to 500 mu M against murine peritoneal macrophages. In vitro studies suggested that 4f may act by a dual effect, by releasing nitric oxide after biotransformation and by inhibiting cysteine protease CPB (IC50: 4.5 mu M). In vivo studies using an acute model of infection showed that compound 4f at 7.7 mg/Kg reduced similar to 90% of parasite burden in the liver and spleen of L. infantum-infected BALB/c mice. Altogether, these outcomes highlight furoxan 4f as a promising compound for further evaluation as an antileishmanial agent. (AU)

• FAPESP's process: 16/06931-4 - Biodiversity of marine algae and metabolites of economical impact
• Grantee: Pio Colepicolo Neto
• Support Opportunities: BIOTA-FAPESP Program - Thematic Grants
• FAPESP's process: 17/03552-5 - Leishmaniasis: from screening to the study of mechanisms of action, a contribution to the discovery of new bioactive molecules
• Grantee: Marcia Aparecida Silva Graminha
• Support Opportunities: Regular Research Grants