Parasitological profiling shows 4(1H)-quinolone derivatives as new lead candidates for malaria

European Journal of Medicinal Chemistry Reports

Glaucius Oliva¹  Fabio C. Cruz¹  Svetlana Antonyuk¹  Everton M. da Silva²  Suzete M. Almeida²  Arlene G. Corrêa³  Daniel Y. Bargieri⁴  Juliana Calit⁴  Anna C.C. Aguiar⁵  S. Samar Hasnain⁶  Dhelio B. Pereira⁶  Kangsa Amporndanai⁶  Rafael V.C. Guido⁷  Guilherme E. Souza⁷  Camila L. Zanini⁷  Juliana O. de Souza⁷ 

[1] Systems Biology, Institute of Systems, Molecular and Integrative Biology, University of Liverpool, Crown Street, Liverpool, L69 7ZB, United Kingdom;Centre of Excellence for Research in Sustainable Chemistry, Department of Chemistry, Federal University of São Carlos, São Carlos, SP, 13565-905, Brazil;Department of Pharmacology, Federal University of São Paulo, Rua Botucatu 862, São Paulo, SP, 04023-062, Brazil;Institute of Biomedical Sciences, University of São Paulo, São Paulo, SP, 05508-000, Brazil;Malaria Outpatient Clinic, Tropical Medicine Research Center. Av. Guaporé, 415 - Lagoa, 76812-329, Porto Velho, RO, Brazil;;Molecular Biophysics Group, Department of Biochemistry &São Carlos Institute of Physics, University of São Paulo, Av. Joao Dagnone, 1100 Jardim Santa Angelina, São Carlos, SP, 13563-120, Brazil;

关键词: Malaria;    Plasmodium falciparum;    Plasmodium vivax;    Inhibitor;    4(1H)-Quinolone;    Cytochrome bc1 complex;   

DOI  :  

来源: DOAJ

【 摘 要 】

4(1H)-quinolone is an attractive template for antimalarial drug discovery campaigns. Given the current global increase in drug and insecticide resistance, the discovery of new antimalarial drugs is an urgent goal for the fight against malaria. Here, the synthesis and antiplasmodial profiling of a series of 4(1H)-quinolone derivatives are reported. Four compounds showed inhibitory activities in submicromolar range against a panel of sensitive and resistant Plasmodium falciparum strains (IC50s ​= ​0.07–0.48 ​μM) and neither cytotoxic (SI ​> ​210) nor hemolytic activities were observed. Representative compounds of the series showed slow-acting in vitro inhibition, enhanced inhibitory activities over the later erythrocytic forms of the parasite, and submicromolar activity against the ookinete stage (IC50ook ​= ​0.7 ​μM). Evaluation of the mechanism of action indicated that the frontrunner, compound 4 (LSPN182), is a potent (IC50Pfbc1 ​= ​0.5 ​μM) and selective (SI ​> ​120) inhibitor for the cytochrome bc1 complex of P. falciparum. Moreover, the frontrunner exhibited considerable activity against clinical field isolates of both P. falciparum and P. vivax (IC50s of 0.5 and 1.5 ​μM, respectively), a noticeable synergic inhibitory behavior when combined with the antimalarial proguanil (FICindex < 1), and modest oral efficacy at 50 ​mg/kg in a mouse model of P. berghei malaria (45% reduction in parasitemia on day 7 postinfection). Hence, the 4(1H)-quinolone derivatives are attractive chemotypes endowed with relevant in vitro, ex vivo, and in vivo activity.

【 授权许可】

Unknown