geldanamycin and Malaria--Falciparum

Atovaquone belongs to a naphthoquinone class of drugs and is used in combination with proguanil (Malarone) for the treatment of acute, uncomplicated malaria caused by Plasmodium falciparum (including chloroquine-resistant P. falciparum/P. vivax). Numerous quinone-derived compounds have attracted considerable attention in the last few decades due to their potential in antimalarial drug discovery. Several semi-synthetic derivatives of natural quinones, synthetic quinones (naphtho-/benzo-quinone, anthraquinones, thiazinoquinones), and quinone-based hybrids were explored for their in vitro and in vivo antimalarial activities. A careful literature survey revealed that this topic has not been compiled as a review article so far. Therefore, we herein summarise the recent discovery (the year 2009-2020) of quinone based antimalarial compounds in chronological order. This compilation would be very useful towards the exploration of novel quinone-derived compounds against malarial parasites with promising efficacy and lesser side effects.

Topics: Antimalarials; Dose-Response Relationship, Drug; Malaria, Falciparum; Molecular Structure; Parasitic Sensitivity Tests; Plasmodium falciparum; Quinones; Structure-Activity Relationship

Whole-cell high-throughput screening of the AstraZeneca compound library against the asexual blood stage of Plasmodium falciparum (Pf) led to the identification of amino imidazoles, a robust starting point for initiating a hit-to-lead medicinal chemistry effort. Structure-activity relationship studies followed by pharmacokinetics optimization resulted in the identification of 23 as an attractive lead with good oral bioavailability. Compound 23 was found to be efficacious (ED90 of 28.6 mg·kg(-1)) in the humanized P. falciparum mouse model of malaria (Pf/SCID model). Representative compounds displayed a moderate to fast killing profile that is comparable to that of chloroquine. This series demonstrates no cross-resistance against a panel of Pf strains with mutations to known antimalarial drugs, thereby suggesting a novel mechanism of action for this chemical class.

Topics: Animals; Antimalarials; Benzimidazoles; Biological Availability; Cell Line, Tumor; Cell Survival; High-Throughput Screening Assays; Humans; Inhibitory Concentration 50; Malaria, Falciparum; Mice; Plasmodium falciparum; Small Molecule Libraries; Structure-Activity Relationship