Further Investigations of Nitroheterocyclic Compounds as Potential Antikinetoplastid Drug Candidates

Abstract

Due to the lack of specific vaccines, management of the trypanosomatid-caused neglected tropical diseases (sleeping sickness, Chagas disease and leishmaniasis) relies exclusively on pharmacological treatments. Current drugs against them are scarce, old and exhibit disadvantages, such as adverse effects, parenteral administration, chemical instability and high costs which are often unaffordable for endemic low-income countries. Discoveries of new pharmacological entities for the treatment of these diseases are scarce, since most of the big pharmaceutical companies find this market unattractive. In order to fill the pipeline of compounds and replace existing ones, highly translatable drug screening platforms have been developed in the last two decades. Thousands of molecules have been tested, including nitroheterocyclic compounds, such as benznidazole and nifurtimox, which had already provided potent and effective effects against Chagas disease. More recently, fexinidazole has been added as a new drug against African trypanosomiasis. Despite the success of nitroheterocycles, they had been discarded from drug discovery campaigns due to their mutagenic potential, but now they represent a promising source of inspiration for oral drugs that can replace those currently on the market. The examples provided by the trypanocidal activity of fexinidazole and the promising efficacy of the derivative DNDi-0690 against leishmaniasis seem to open a new window of opportunity for these compounds that were discovered in the 1960s. In this review, we show the current uses of nitroheterocycles and the novel derived molecules that are being synthesized against these neglected diseases.

Using 5-Nitroimidazole Derivatives against Neglected Tropical Protozoan Diseases: Systematic Review

“…Of these, approximately 50,000 to 90,000 are VL, and 600,000 to 1 million are various forms of CL and MCL. The annual death toll from leishmaniasis disease is between 26,000 and 65,000 [23,24]. Additionally, the economic impact per year has been estimated at 1.4 million Disability-Adjusted Life Years (DALYs), primarily associated with VL [8].…”

Polyamine Metabolism for Drug Intervention in Trypanosomatids

“…Sleeping sickness is currently being treated with the combination therapy NECT, comprising nifurtimox and the ornithine analog α-difluoromethylornithine (DFMO; eflornithine) (Figure 1), and recently, fexinidazole has been successfully included [17]. For Chagas disease, the nitroheterocycles nifurtimox and benznidazole have been the two drugs of choice for several decades with good results [18].…”

In Vitro and In Vivo Trypanocidal Efficacy of Nitrofuryl- and Nitrothienylazines

“…The potential toxicity phenomena associated with nitroheterocycles limited their use and even prohibited their inclusion in drug discovery programs. Nevertheless, the urgent need for novel trypanocidal agents and the approval of fexinidazole have led to renewed interest in these scaffolds …”

“…However, caution is advised not to develop too many nitroheterocycles against trypanosomatid diseases at once because the high dependency on prodrug activation by nitroreductase I can lead to drug resistance; thus, it is essential to determine the activation mechanism of new nitroheterocyclic compounds in the early stage of drug discovery …”

“…24 However, caution is advised not to develop too many nitroheterocycles against trypanosomatid diseases at once because the high dependency on prodrug activation by nitroreductase I can lead to drug resistance; thus, it is essential to determine the activation mechanism of new nitroheterocyclic compounds in the early stage of drug discovery. 24 Interestingly, Trypanosomas are one of the very few genera that do not use the glutathione/glutathione reductase system for protection against oxidative stress but rather rely on trypanothione/trypanothione reductases. 25,26 Nitrofurans with aromatic and heterocyclic substituents have been found to inhibit T. congolense trypanothione reductase.…”