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Front. Pharmacol. | doi: 10.3389/fphar.2019.00873

Chagas disease treatment and synthetic drugs: A challenge that remains

  • 1Aggeu Magalhães Institute (IAM), Brazil
  • 2Laboratório de Parasitologia, Federal University of Pernambuco, Brazil
  • 3Departamento de Ciências Farmacêuticas, Laboratório de Planejamento e Síntese em Química Medicinal, Federal University of Pernambuco, Brazil
  • 4Departamento de Ciências Farmacêuticas, Laboratório de Imunopatologia e Biologia Molecular, Federal University of Pernambuco, Brazil
  • 5Departamento de Ciências Farmacêuticas, Federal University of Pernambuco, Brazil

Chagas disease is a neglected disease caused by Trypanosoma cruzi, a protozoan of the family Trypanosomatidae. It is an important public health issue because it affects populations who have lower socioeconomic resources and less access to health. Estimates suggest that 6 to 7 million people worldwide have the disease, and that it is mainly distributed among the 21 countries of Latin America, where more than 1 million of those occur in Brazil (1).
Since its discovery in 1909, several compounds have been tested as candidates for treatment, such as: arsenic, fuchsin, bismuth, antihistamines, amphotericin B, antibiotics, and others (2). Currently, the treatment is based on the administration of two drugs: benzonidazole (Figure 1A) and nifurtimox (Figure 1B). They are more effective in the acute phase over the chronic phase and have a high toxicity rate (3).
According to the Centers for Disease Control and Prevention (4), the adverse effects caused by the treatment’s great toxicity are mainly gastrointestinal, including vomiting, abdominal pain, anorexia and weight loss regarding nifurtimox, and allergic dermatitis, insomnia and peripheral neuropathy related to benzonidazole. Since the discovery of these two compounds, no other drug has been approved for Chagas disease treatment in the last 40 years (5). The treatment is indicated for all individuals with the acute infection, in cases of congenital infection, in immunosuppressed patients and children with the chronic form of the disease (6).
According to the Drugs for Neglected Diseases Initiative (7), the current treatment presents issues, such as long-term (30-60 days), dose-dependent toxicity, low adherence rate, and lack of a pediatric formulation. In 2011, a formulation to be used in children under 2 years of age produced by the Pharmaceutical Laboratory of Pernambuco and registered by the National Sanitary Surveillance Agency of Brazil was launched with the support of DNDi. Some of the advantages linked to this formulation are: more safety for this group; it is a tablet readily dispersible in liquids, which facilitates administration; the need for fractionation is only required in special cases (premature infants weighing less than 2.5 kg); and the fact that the drug can be safely administered at home throughout the treatment (twice a day for 60 days).
The poor access to medication is another issue related to Chagas disease’s treatment. Some countries in non-endemic areas such as Spain have reported the shortage of the drug (8). The absence was due mainly to the increased demand of the drug that was not being followed by its production (9). This demonstrates the need of a management plan for Chagas disease treatment, which still remains in a state of neglection.
Besides that, clinical studies with new candidates for Chagas disease treatment require both great time and effort and diagnosis limitations such as the lack of tools which can demonstrate parasitological cure in the chronic phase have not yet been overcome (10). The lack of consensus has also been reported regarding the efficacy of the chronic disease’s treatment, both in experimental models and in studies with chronic patients (11). In 2015, a multicenter randomized study with chronical chagasic patients was conducted by researchers in Brazil, Colombia, El Salvador, Argentina and Bolivia. The study Benzonidazole Evaluation For Interrupting Trypanosomiasis (BENEFIT), has evaluated benzonidazole’s efficacy in preventing the progression to chronic chagasic cardiopathy and death of patients, following 2,854 individuals for 5 years. Although progress has been made regarding the understanding of benzonidazole’s effect during treatment, no reduction of heart disease was observed in treated patients (12).
Another clinical trial with Chagas disease patients is the Benznidazole New Doses Improved Treatment & Therapeutic Associations (BENDITA) study (13). The aim of this trial was to find new dosages of the current treatment without decreasing its effectiveness, whereas a combined treatment with fosravuconazole, a broad-spectrum antifungal drug, was also tested. They found that the 2-week treatment is promising since it is 4 times shorter than the standard treatment, and all patients completed the course. Although, the data of the combination arms (benznidazole combined with fosravuconazole) are still being analyzed. This lower dosage and time of treatment would facilitate treatment adherence, since it would consequently reduce adverse effects.
Challenges in the study of effective drugs for Chagas disease
One of the main focuses on Chagas disease research has been the development of effective control measures (14). However, there are some obstacles when it comes to the development of effective compounds, such as the difficulty of standardizing in vivo and in vitro tests for their screening and the absence of efficacy and cure criteria markers of treatment (15, 16). In order to evaluate cure criteria, PCR and serological conversion are used to assess the parasite load (17, 18). However, serological conversion may take years to be achieved, which requires new sensitive markers of efficacy (19). There are a number of questions that can only be answered by improving experimental research on drugs for Chagas disease, including better in vivo models that mimetize the disease and knowing what the cure criteria for these models would be (20).
Regarding the treatment, DNDi has indicated the criteria which are considered acceptable and ideal for Chagas disease, some of them are: to be active against all strains of T. cruzi; the clinical efficacy has to be superior to benzonidazole in all phases of the disease; it must not have contraindications or pharmacological interactions; and it has to be administered orally (21).
Therefore, difficulties do exist and there is a need to overcome them in order to discover a suitable treatment for the disease.
Synthetic drugs and new therapeutic approaches for Chagas disease
The search for new drugs against Chagas disease has evolved appreciably in recent years (22). In this context, different strategies of drug design and discovery are used and have proved to be effective, such as molecular simplification, privileged structures, pro-drugs, quantitative structure-activity relationship (QSAR), molecular hybridization, bioisosterism and molecular docking (17, 23, 24, 25).
For studies to progress, it is important to look for specific molecular targets of the parasite, and most of them are enzymes (26, 27). Thus, several molecules have been explored in medicinal chemistry programs applying drug-planning methods based on receptor and ligand structures (28). Some important T. cruzi enzymatic targets such as trans-sialidase, nitroreductase type 1 (NTR) and cruzain are investigated (29, 30, 31, 32).
Trans-sialidase is an enzyme which is absent in mammalian cells and is involved in parasite’s evasion from the immune system, more specifically from the complement system, as well as in adhesion and invasion onto host cells, decrease of T and B lymphocytes and thymic atrophy (33, 34, 35). The sialylmimetic neoglycoconjugates were also investigated, where the 1,2,3-triazole linked sialic acid-6-O-galactose and the sialic acid-galactopyranoside compound (Figure 1C) stood out regarding their activities (36). Conjugation of lactitol analogues with polyethylene glycol has also been shown to be effective in inhibiting this enzyme during in vitro studies (37). More recently, a database screening of more than 4 million compounds has found 2 molecules, ZINC13359679 (Figure 1D) and ZINC02576132 (Figure 1E), as the most promising candidates that could inhibit this enzyme (38). When computational strategies screened more than 3.000 drugs approved by the FDA, and in vitro and in vivo tests were performed, it was seen that the anti-inflammatory sulfasalazine (Figure 1F) can be used as a lead to design new enzyme inhibitor drugs (39). Recently it was found that molecules containing amide, hydroxyl and carboxylic acid radicals in their aromatic rings can enhance the biological activity of these enzyme inhibitors, which may lead to a better rational drug design (40).
NTR is an enzyme involved in the activation of nitroheterocyclic compounds, such as benzonidazole and nifurtimox (41). Recent studies have shown its in vitro and in vivo potential in studies of absorption, distribution, metabolism, and excretion (ADME) of this enzyme inhibitors (42, 43, 44). Corroborating this idea, a study demonstrated that NTR inhibitors were more effective than inhibitors of ergosterol synthesis when tests using amastigotes from representatives of each Discrete Type Unit (DTU) were performed (45). DTU is a set of genetically similar T. cruzi populations which can be identified by common genetic/ molecular/immunological markers (46).
The cruzain, also called cruzipain or GP57/51, is the most abundant protein in the T. cruzi cysteine protease family and is the key enzyme for the parasite’s intracellular replication (47) and in its escape from the host’s immune system, representing a molecular target to design new antiparasitic drugs (48, 49, 50). In vitro tests performed by our research group with thiazide derivatives, aryl thiosemicarbazones and aryl-4-thiazolinones had an effective anti-T. cruzi activity (51) even on a nanomolar scale, confirmed by the high affinity of these molecules during docking studies. The most potent and well-known inhibitor of this enzyme is K777 (Figure 1G), which is about to enter clinical studies (52, 53). In the same way as for trans-sialidase, a screening with drugs which were approved by the Food and Drug Administration (FDA) was conducted for cruzain and found that four compounds could be used as a basis to design new drugs, namely etofylline clofibrate (Figure 1H, antilipemic) and piperacillin, cefoperazone, and flucloxacillin (antibiotics, Figures 1I, J, K, respectively) (54 Palos et al., 2017).
Conclusion and perspectives
Opportunities for drug planning studies are promising, especially with the recent decades advances in molecular biology; cell, medicinal and computational chemistry and planned organic synthesis. For a thorough and correct election of a drug candidate against Chagas disease, further activity studies within preclinical trials (such as in vivo testing) and clinical trials are needed. However, there is still a large gap regarding the standardization of these tests as well as a lack of biomarkers and cure criteria. With the combination of different techniques to discover new drugs, we hope that a refinement in search for a new therapy against Chagas disease will be facilitated, leading to the achievement of this goal.

Keywords: Chagas disease - 1, Drug Development, drug target, Trypanosoma cruzi, Benzonidazole

Received: 17 Apr 2019; Accepted: 08 Jul 2019.

Edited by:

Mauro M. Teixeira, Federal University of Minas Gerais, Brazil

Reviewed by:

Frederick S. Buckner, University of Washington, United States  

Copyright: © 2019 Silva, Brelaz de Castro, Leite, Pereira and Hernandes. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

* Correspondence: Mx. Ana Catarina C. Silva, Aggeu Magalhães Institute (IAM), Recife, Brazil, catarinacristovao@outlook.com