Current and Future Prospects of Nitro-compounds as Drugs for Trypanosomiasis and Leishmaniasis

Abstract

Interest in nitroheterocyclic drugs for the treatment of infectious diseases has undergone a resurgence in recent years. Here we review the current status of monocyclic and bicyclic nitroheterocyclic compounds as existing or potential new treatments for visceral leishmaniasis, Chagas' disease and human African trypanosomiasis. Both monocyclic (nifurtimox, benznidazole and fexinidazole) and bicyclic (pretomanid (PA-824) and delamanid (OPC-67683)) nitro-compounds are prodrugs, requiring enzymatic activation to exert their parasite toxicity. Current understanding of the nitroreductases involved in activation and possible mechanisms by which parasites develop resistance is discussed along with a description of the pharmacokinetic / pharmacodynamic behaviour and chemical structure-activity relationships of drugs and experimental compounds.

Parasite, Compartments, and Molecules: Trick versus Treatment on Chagas Disease

“…Alternative enzymes have been associated with the reduction of nitro compounds in T. cruzi, indicative of a secondary action for these drugs, and further studies about the molecular mechanisms involved must be performed. The high trypanocidal activity together with the identification of exclusive nitroreductases in trypanosomatids supports the hypothesis of selectivity [63].…”

“…Bz and Nif are considered prodrugs that require activation by nitroreductases-NTR-I, an oxygen insensitive class catalyzing the two-electron reduction of the nitro group and NTR-II, an oxygen-sensitive class catalyzing one-electron reduction [62]. The mechanistic proposal of Nif involves nitroanion radical metabolization by NTR-II, followed by reoxidation by molecular oxygen to form superoxide anion (•O 2 − ), which is converted to hydrogen peroxide (H 2 O 2 ) under catalysis by SOD (Figure 4) [63]. On the other hand, low molecular weight thiol reduction together with no redox cycling in trypanocidal doses supported the hypothesis that oxidative effect was not involved in the parasite killing by Nif [64].…”

Challenges in Chagas Disease Drug Development

“…Fexinidazole, an NTR-1-activated 5-nitroimidazole pro-drug [ 31 ], has been shown to outperform both benznidazole and nifurtimox as a curative treatment for experimental T. cruzi infections [ 34 ] ( Figure 2 A,B, as example), and a clinical trial to assess efficacy and tolerability against patients with asymptomatic chronic infections has been undertaken [ 35 ]. In addition, there have also been a number of recent studies reporting encouraging preliminary data on the antiparasite activities of other novel nitroaromatics [ 88 ], and of a new generation of diverse organometallic compounds [ 89 , 90 , 91 , 92 ].…”

Activity profile of two 5-nitroindazole derivatives over the moderately drug-resistant Trypanosoma cruzi Y strain (DTU TcII): in vitro and in vivo studies

“…Presently, more than five decades after the introduction of these two medicines, a promising drug candidate for CD therapy is fexinidazole, another nitroheterocyclic compound that is the first all-oral treatment approved for both stages of Trypanosoma brucei gambiense human infection, the most common form of sleeping sickness (Patterson and Wyllie, 2014; WHO, 2019). According to these findings, it is noteworthy to point out that nitroheterocycles are still considered as a tempting group of molecules to be explored for the identification of novel CD treatments (Patterson and Fairlamb, 2018). Several families of synthetic compounds that contain nitro groups in their scaffolds and also commercialized drugs identified by repurposing strategies, such as the 5-nitroimidazole metronidazole, have been recently proposed as putative anti- T. cruzi agents, according to the promising activity they achieved in different experimental models of the disease, both in vitro and in vivo (Simões-Silva et al ., 2017; Thompson et al ., 2017; Almeida et al ., 2018; Arias et al ., 2018; Leite et al ., 2018; Palace-Berl et al ., 2018; Chaves e Mello et al ., 2020).…”