Recent Progress in the Development of Indole-Based Compounds Active against Malaria, Trypanosomiasis and Leishmaniasis

Human protozoan diseases represent a serious health problem worldwide, affecting mainly people in social and economic vulnerability. These diseases have attracted little investment in drug discovery, which is reflected in the limited available therapeutic arsenal. Authorized drugs present problems such as low efficacy in some stages of the disease or toxicity, which result in undesirable side effects and treatment abandonment. Moreover, the emergence of drug-resistant parasite strains makes necessary an even greater effort to develop safe and effective antiparasitic agents. Among the chemotypes investigated for parasitic diseases, the indole nucleus has emerged as a privileged molecular scaffold for the generation of new drug candidates. In this review, the authors provide an overview of the indole-based compounds developed against important parasitic diseases, namely malaria, trypanosomiasis and leishmaniasis, by focusing on the design, optimization and synthesis of the most relevant synthetic indole scaffolds recently reported.

Novel K540N Mutation in Plasmodium falciparum Dihydropteroate Synthetase Confers a Lower Level of Sulfa Drug Resistance than Does a K540E Mutation

ABSTRACTSulfadoxine (SDX) and sulfamethoxazole (SMX) each inhibit thePlasmodium falciparumdihydropteroate synthetase (PfDHPS), and certain point mutations in this enzyme yield the drug-resistant parasite. Using a simpleEscherichia colimodel system, we describe here the effect of the recently reported novel K540N mutation in PfDHPS on the level of SDX/SMX resistance. The survival rate of the transformedE. coli(DHPS-deficient strain) under different SDX or SMX concentrations revealed that the K540N mutation confers a lower level of drug resistance than its contemporary K540E mutation. Further, SMX was more effective than SDX in theE. colisystem.

Metabolomic analysis of protozoan parasites

Protozoan parasites cause a number of important diseases in humans, including malaria, African trypanosomiasis, Chagas disease and the leishmaniases. Current therapeutics for these diseases are limited and their effectiveness is being further undermined by the emergence of drug-resistant parasite strains. Parasite genome sequencing projects have provided new insights into the metabolic capacity of these pathogens and have highlighted potential drug targets. However, these genome-based reconstructions of metabolic networks are incomplete and we still have only a limited understanding of the metabolic requirements of these pathogens during infection. Metabolomics has emerged as a powerful new tool for investigating parasite metabolism and host responses, complementing more established omics technologies as well as being useful as a stand-alone technique.

The role of drugs in the control of parasitic nematode infections: must we do without?

Parasitic helminths (worms) cause serious infectious diseases in humans and domestic animals. Control of these infections relies mostly on chemotherapeutics (the anthelmintics), but resistance has developed against most of these broad-spectrum drugs in many parasite species. These resistant parasites are being used to elucidate the molecular mechanisms of drug resistance and drug action. This has led to the development of sensitive assays to detect resistant parasites, but this has not delayed the emergence of additional drug resistant parasite populations. Therefore, as development of new drugs by pharmaceutical companies is slow, we may have to be prepared for a time when broad-spectrum drugs are no longer effective, especially against worms of sheep.