Recent progress in the development of anti-malarial quinolones

Abstract

Available anti-malarial tools have over the ten-year period prior to 2012 dramatically reduced the number of fatalities due to malaria from one million to less than six-hundred and thirty thousand. Although fewer people now die from malaria, emerging resistance to the first-line anti-malarial drugs, namely artemisinins in combination with quinolines and arylmethanols, necessitates the urgent development of new anti-malarial drugs to curb the disease. The quinolones are a promising class of compounds, with some demonstrating potent in vitro activity against the malaria parasite. This review summarizes the progress made in the development of potential anti-malarial quinolones since 2008. The efficacy of these compounds against both asexual blood stages and other stages of the malaria parasite, the nature of putative targets, and a comparison of these properties with anti-malarial drugs currently in clinical use, are discussed.

Figure 1

Schematic life cycle of malaria parasite. (A) Liver phase, (B) Blood phase, (C) Mosquito phase. The cycle progresses from (A) to (B), and then to (C).

Figure 2

Structures of chloroquine (1), artemisinin (2) and its derivatives: dihydroartemisinin (3), artemether (4), arteether (5), artesunate (6), and primaquine (7).

Figure 3

The quinolone scaffold.

Figure 4

Structures of endochin and its derivatives.

Figure 5

Structure of HDQ and its derivatives.

Figure 6

Structure of acridinone and analogues.

Figure 7

Structures of carboxylquinolones.

Figure 8

All structures, and their potencies.