Defining the targets of antiparasitic compounds

Abstract

The treatment of major human parasitic infections is dependent on drugs that are plagued by issues of drug resistance. New chemotherapeutics with novel mechanisms of action (MOA) are desperately needed to combat multi-drug-resistant parasites. Although widespread screening strategies are identifying potential new hits for development against most major human parasitic diseases, in many cases such efforts are hindered by limited MOA data. Although MOA data are not essential for drug development, they can facilitate compound triage and provide a mechanism to combat drug resistance. Here we describe and discuss methods currently used to identify the targets of antiparasitic compounds, which could circumvent this bottleneck and facilitate the development of new antiparasitic drugs.

Anti-trypanosomatid drug discovery: an ongoing challenge and a continuing need

“…However, chemical optimization of these phenotypic start points can be challenging due, for example, to pharmacokinetic issues, insufficient potency or off-target toxicity. Without target deconvolution, that is, the identification of the molecular target, target-based screening cannot be used to find alternative chemical scaffolds that might overcome these issues, and structure-based drug design cannot be used for compound optimization [126]. In addition, although not essential, knowledge of the mode-of-action can facilitate the design of combination therapies, surveillance for the emergence and spread of resistance and assessment of the risk of resistance.…”

Deguelin exerts potent nematocidal activity via the mitochondrial respiratory chain

“…Given the toxicity of deguelin on C. elegans,l o s so f function studies in this model organism would aid in identifying and proving the target of deguelin in nematodes. Although not essential for drug discovery and development, understanding the mode of action of a drug on a target organism will aid in predicting aspects of host toxicity, adverse effects, and/or potential modes of drug resistance (104).…”

Retracted Article: The synthesis and biological activity of marine alkaloid derivatives and analogues

“…184 According to the World Health Organization, there are more than 100 species of malaria parasites that cause malaria. [185][186][187][188] However, only a few species of plasmodium have attracted research attention, including Plasmodium falciparum, Plasmodium malariae, Plasmodium vivax, Plasmodium knowlesi and Plasmodium ovale. Malaria, caused by malignant protozoa, is a severe disease and can cause other syndromes.…”

“…During the synthesis route selection of 3-APA analogues, the specic synthesis operations were carried out as shown in Scheme 9. Diols (compounds 179-182) with different length carbon chains were used as the starting materials of the reaction, and their single hydroxyl groups were selectively protected to obtain the corresponding monohydropyronic acetals (compounds [183][184][185][186]. Then, the hydroxyl groups of compounds 183-186 were further protected to obtain the compounds 187-190.…”