| Full text | |
| Author(s): Show less - |
do Espirito Santo, Rafael Dias
;
Arenas Velasquez, Angela Maria
;
Gushiken Passianoto, Luana Vitorino
;
Lopera Sepulveda, Alex Arbey
;
Clementino, Leandro da Costa
;
Assis, Renata Pires
;
Baviera, Amanda Martins
;
Kalaba, Predrag
;
dos Santos, Fabio Neves
;
Eberlin, Marcos Nogueira
;
Jose da Silva, Gil Valdo
;
Zehl, Martin
;
Lubec, Gert
;
Silva Graminha, Marcia Aparecida
;
Perez Gonzalez, Eduardo Rene
Total Authors: 15
|
| Document type: | Journal article |
| Source: | EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY; v. 171, p. 13-pg., 2019-06-01. |
| Abstract | |
Leishmaniasis is a group of diseases caused by protozoan parasites from the genus Leishmania. There are estimated 1.3 million new cases annually with a mortality of 20,000-30,000 per year, when patients are left untreated. Current chemotherapeutic drugs available present high toxicity and low efficacy, the latter mainly due to the emergence of drug-resistant parasites, which makes discovery of novel, safe, and efficacious antileishmanial drugs mandatory. The present work reports the synthesis, characterization by ESI-MS, H-1 and C-13 NMR, and FTIR techniques as well as in vitro and in vivo evaluation of leishmanicidal activity of guanidines derivatives presenting lower toxicity. Among ten investigated compounds, all being guanidines containing a benzoyl, a benzyl, and a substituted phenyl moiety, LQOF-G2 (IC50-ama 5.6 mu M: SI = 131.8) and LQOF-G7 (IC50-ama 7.1 mu M; SI = 87.1) were the most active against L. amazonensis intracellular amastigote, showing low cytotoxicity to the host cells according to their selectivity index. The most promising compound, LQOF-G2, was further evaluated in an in vivo model and was able to decrease 60% of the parasite load in foot lesions at a dose of 0.25 mg/kg/day. Moreover, this guanidine derivative demonstrated reduced hepatotoxicity compared to other leishmanicidal compounds and did not show nephrotoxicity, as determined by the analyses of biomarkers of hepatic damage and renal function, which make this compound a potential new hit for therapy against leishmaniasis. (C) 2019 Elsevier Masson SAS. All rights reserved. (AU) | |
| FAPESP's process: | 13/24487-6 - Study of reactions of clean synthesis and chemical modification of the biodiesel and fusel oil for preparation of organic carbonate and carbamates using carbon dioxide in the presence of organocatalysts and heterogeneous catalysts |
| Grantee: | Eduardo Rene Perez Gonzalez |
| Support Opportunities: | Regular Research 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 |
| FAPESP's process: | 13/08248-1 - Leishmaniasis and bioinorganic compounds containing Au(I) and Pd(II): antileishmanial activities, mechanims of action and putative new drug targets |
| Grantee: | Marcia Aparecida Silva Graminha |
| Support Opportunities: | Regular Research Grants |
| FAPESP's process: | 16/19289-9 - Characterization of Mechanism of cell death potentially induced by a binuclear antileishmanial cyclopalladated CP2: a contribution to the rational drug development |
| Grantee: | Angela Maria Arenas Velásquez |
| Support Opportunities: | Scholarships in Brazil - Post-Doctoral |