Detalhes bibliográficos
| Resumo: | We present insights into the mechanism of action of marinoquinolines (MQ), a novel class of lead candidates. Using a divergent synthetic approach, we developed a series of 20 new analogues with fluorescence properties. Structure–activity relationships analysis identified 19 as an attractive compound showing a combination of favorable in vitro (IC503D7= 0.28 μM; CC50HepG2= 53 μM), ex vivo (EC50Pf= 1.2 μM; EC50Pv= 0.53 μM), in vivo (3 × 50 mg/kg oral dose resulted in a 96% reduction in parasitemia in Plasmodium berghei-infected mice), physicochemical (Sol7.4= 171 μM; LogD7.4= 3.9), and pharmacokinetic (P_app = 9.4 × 10–6cm/s, human Clinthep,mic= 0.61–0.68 μL min–1mg–1) properties. Compound 19 selectively accumulates in infected erythrocytes, enters the digest vacuole and inhibits Plasmodium falciparum proteolytic activity, suggesting that MQs act as protease inhibitors. These findings strengthen the evidence that MQs are promising lead candidates for antimalarial drug discovery. |
|---|
| Autores principais: | Santos Barbosa, Patricia |
|---|
| Outros Autores: | Souza, Guilherme Eduardo; Maluf, Sarah El Chamy; Bonatto, Vinícius; Moura, Caio Silva; Mendes, Giovana Rossi; Valdes, Talita Alvarenga; Annunciato, Yasmin; Rossetto, Barbara dos Santos; Ventura, Priscilla Dantas de Souza; Ortin, Gilberto Gaspar Duarte; da Silva, Wellington; Icimoto, Marcelo Yudi; Ferreira, Amália dos Santos; Cruz, Fabio C.; Teles, Carolina B. G.; Pereira, Dhelio B.; Cassiano, Gustavo Capatti; Santana, Sofia; Prudêncio, Miguel; Barbosa, Camila S.; Moura, Igor M. R.; Giampauli, Renan Marcel; De Sousa, Irene Layane; Rocco, Silvana Aparecida; Gazarini, Marcos L.; Correia, Carlos Roque Duarte; Aguiar, Anna Caroline Campos; Guido, Rafael Victorio Carvalho |
|---|
| Assunto: | Molecular Medicine Drug Discovery |
|---|
| Ano: | 2025 |
|---|
| País: | Portugal |
|---|
| Tipo de documento: | artigo |
|---|
| Tipo de acesso: | acesso aberto |
|---|
| Instituição associada: | Universidade Nova de Lisboa |
|---|
| Idioma: | inglês |
|---|
| Origem: | Repositório Institucional da UNL |
|---|