Discovery of marinoquinoline derivatives as Plasmodium falciparum inhibitors

Author(s)

Guilherme Eduardo de Souza

• Document type: Doctoral Thesis
• Press: São Carlos.
• Institution: Universidade de São Paulo (USP). Instituto de Física de São Carlos (IFSC/BT)
• Defense date: 2022-04-06

Examining board members

Rafael Victório Carvalho Guido; Nubia Boechat Andrade; Daniel Youssef Bargieri; Roberto Rudge de Moraes Barros; Fábio Trindade Maranhão Costa

• Advisor: Rafael Victório Carvalho Guido; Anna Caroline Campos Aguiar

Abstract

Malaria is the tropical disease with the highest global killing rate. The emergence of resistance to the first line therapies confirms the necessity of the discovery and development of new drug candidates. The objective of this work was the discovery of new marinoquinoline (pyrrolo[2,3-c]quinoline) derivatives as inhibitors of the development of Plasmodium falciparum asexual form. In this sense, the positions 1, 3, 4 and 7 of the marinoquinolinic scaffold were investigated for the discovery of potent and selective derivatives. A total of 167 compounds were synthesized and assessed for the in vitro inhibitory potency, cytotoxicity, and selectivity. Structure-activity relationship studies led to the identification of compound 90 as the most potent and selective derivative of the series (IC503D7 = 0,14 μM; IC50HepG2 > 12,5 μM; SI > 89). Marinoquinolines were shown to possess low propensity of selecting resistant parasites. Confocal fluorescence microscopy showed that marinoquinolines are distributed diffusely within P. falciparum. Mechanism of action investigation studies indicated that marinoquinolines did not inhibit isoprenoid biosynthesis, however they were inhibitors of the cytoplasmatic cysteine-proteases of the parasite. The evaluation of the series´ representative compound 151 against a panel of resistance strains provided new evidence that marinoquinolines have a unique antiplasmodial mechanism of action when compared to antimalarials as chloroquine, pyrimethamine, sulfadoxine, mefloquine, atovaquone and MMV692848. Moreover, 151 eliminated the parasites resistant to these antimalarials. In conclusion, the marinoquinoline series has considerable potential, demonstrated by the high potency and selectivity of the series´ representatives. In addition, these compounds showed low cytotoxic effect in hepatic cells, different mechanism of action compared to the standard antimalarials, fast-acting inhibition of parasite growth and pronounced inhibitory activity against resistant strains of the parasite. Therefore, the antiplasmodial profiling of the marinoquinoline series supports the rational design of new derivatives with optimized properties aiming at the development of the next generation of antimalarial drugs. (AU)

• FAPESP's process: 18/07287-7 - Discovery of Acridine and Marinoquinoline Derivatives as Plasmodium falciparum Inhibitors
• Grantee: Guilherme Eduardo de Souza
• Support Opportunities: Scholarships in Brazil - Doctorate