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

Author(s):Show less -

de Souza, Juliana O. ; Almeida, Suzete M. ; Souza, Guilherme E. ; Zanini, Camila L. ; da Silva, Everton M. ; Calit, Juliana ; Bargieri, Daniel Y. ; Amporndanai, Kangsa ; Antonyuk, Svetlana ; Hasnain, S. Samar ; Cruz, Fabio C. ; Pereira, Dhelio B. ; Oliva, Glaucius ; Corre, Arlene G. ; Aguiar, Anna C. C. ; Guido, Rafael V. C.

• Document type: Journal article
• Source: EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY REPORTS; v. 3, p. 16-pg., 2021-12-01.

Abstract

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 (IC(50)s = 0.07-0.48 mu M) 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 mu M). Evaluation of the mechanism of action indicated that the frontrunner, compound 4 (LSPN182), is a potent (IC50Pfbc1 = 0.5 mu M) 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 (IC(50)s of 0.5 and 1.5 mu M, 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. (AU)

• FAPESP's process: 17/26679-0 - 4-Quinolone derivatives as antimalarial drug candidates: Antiplasmodial activity characterization in vitro, in vivo and of the mode of action
• Grantee: Juliana Oliveira de Souza
• Support Opportunities: Scholarships in Brazil - Master
• FAPESP's process: 18/24878-9 - Search for Plasmodium transmission-blocking compounds using new experimental models
• Grantee: Juliana Calit Paim
• Support Opportunities: Scholarships in Brazil - Doctorate (Direct)
• FAPESP's process: 13/07600-3 - CIBFar - Center for Innovation in Biodiversity and Drug Discovery
• Grantee: Glaucius Oliva
• Support Opportunities: Research Grants - Research, Innovation and Dissemination Centers - RIDC
• FAPESP's process: 20/12904-5 - Discovery of Plasmodium falciparum inhibitors from Cerrado plants as lead compounds candidates for malaria: integrated studies of ultra-efficient chromatography, spectroscopy, and biological assays
• Grantee: Rafael Victorio Carvalho Guido
• Support Opportunities: BIOTA-FAPESP Program - Regular Research Grants
• FAPESP's process: 14/50249-8 - Green chemistry: sustainable synthetic methods employing benign solvents, safer reagents, and bio-renewable feedstock
• Grantee: Arlene Gonçalves Corrêa
• Support Opportunities: Research Grants - Research Centers in Engineering Program