Recent advances in antitrypanosomal chemotherapy: patent literature 2002 – 2004

Sleeping sickness and Chagas disease (African and American trypanosomiases, respectively) are protozoan parasitic diseases threatening millions of people in sub-Saharan Africa and Latin America. Trypanosomiases are among the most neglected diseases in the world, desperately lacking financial support for investigation. The current chemotherapy of both diseases is poor and suffers from intolerable side effects and low efficacy in many cases. A review of the patent literature from 2002 to early 2005 claiming molecules with antitrypanosomal activity afforded 36 entries, equally shared between industry and acadaemia. Among the targets validated against trypanosomes, patents dealing with protease inhibitors were the most represented (16 patents). Other targets claimed in the patent literature included membrane architecture (sterol biosynthesis inhibitors, protein farnesyltransferase inhibitors), DNA (DNA binders, tubulin inhibitors) and pyrimidine metabolism (cytidine triphosphate [CTP] synthetase inhibitors). Natural products were also a great source of trypanocidal lead compounds (9 patents). A few patents claiming compounds with antitrypanosomal activity, but disclosing no specific target, were also encountered.     

The proteasome as a potential target for chemotherapy of African trypanosomiasis

Trypanosomes are parasitic protozoans that afflict both humans and livestock in sub‐Saharan Africa. The current chemotherapy of African trypanosomiasis relies on a few drugs, most of which were developed decades ago. Combinations of toxic side effects and poor efficacy of current drugs demand an urgent need for the development of novel and effective therapeutic agents. The proteasome is a multisubunit proteinase complex that plays a critical role in intracellular protein degradation. Despite being essential to all eukaryotic cells, there are significant differences between the trypanosomal and mammalian proteasomes that makes this enzyme complex a promising target for anti‐trypanosomal drug development. In this review article, the structural properties, enzymatic activities, and inhibitor sensitivities of the proteasomes of Trypanosoma brucei and mammalian cells are compared. In addition, the trypanocidal activities of the different classes of proteasome inhibitors are summarized. Drug Dev Res 68:205–212, 2007. © 2007 Wiley‐Liss, Inc.     

Design or screening of drugs for the treatment of Chagas disease: what shows the most promise?

Introduction: Endemic in Latin America, Chagas disease is now becoming a serious global health problem, and yet has no financial viability for the pharmaceutical industry and remains incurable. In 2012, two antimycotic drugs inhibitors of fungal sterol 14α-demethylase (CYP51) – posaconazole and ravuconazole – entered clinical trials. Availability of the X-ray structure of the orthologous enzyme from the causative agent of the disease, protozoan parasite Trypanosoma cruzi, determined in complexes with posaconazole as well as with several experimental protozoa-specific CYP51 inhibitors opens an excellent opportunity to improve the situation.

Areas covered: This article summarizes the information available in PubMed and Google on the outcomes of treatment of the chronic Chagas disease. It also outlines the major features of the T. cruzi CYP51 structure and the possible structure-based strategies for rational design of novel T. cruzi specific drugs.

Expert opinion: There is no doubt that screenings for alternative drug-like molecules as well as mining the T. cruzi genome for novel drug targets are of great value and might eventually lead to groundbreaking discoveries. However, all newly identified molecules must proceed through the long, expensive and low-yielding drug optimization process, and all novel potential drug targets must be validated in terms of their essentiality and druggability. CYP51 is already a well-validated and highly successful target for clinical and agricultural antifungals. With minimal investments into the final stages of their development/trials, T. cruzi-specific CYP51 inhibitors can provide an immediate treatment for Chagas disease, either on their own or in combination with the currently available drugs.     

Novel antineoplastic agents

Cancer chemotherapy represents a major expanding field of academic and industrial research. Many directions have been taken to identify new active compounds as more and more knowledge is gained on the mechanisms of pharmacological action through molecular biology techniques and structural studies at the molecular level. Major aims are to reduce the substantial limitations found in presently used drugs, such as severe toxicity, onset of resistance and lack of selectivity for cancer cells. In this review, we will focus on new patent-disclosed drugs targeted at the nucleic acid DNA and/or DNA-processing enzymes, such as DNA groove binders, alkylators, cleaving agents, topoisomerase I and II directed compounds and antimetabolites. Tubulin inhibitors, such as taxol derivatives, will also be considered. Besides discussing the presently available patent literature and the possible developments connected to that, we will examine the new lines of research that are likely to produce a substantial impact in cancer pharmacology in the near future.     

Novel cruzain inhibitors for the treatment of Chagas' disease

The protozoan parasite Trypanosoma cruzi, the etiological agent of Chagas' disease, affects millions of individuals and continues to be an important global health concern. The poor efficacy and unfavorable side effects of current treatments necessitate novel therapeutics. Cruzain, the major cysteine protease of T. cruzi, is one potential novel target. Recent advances in a class of vinyl sulfone inhibitors are encouraging; however, as most potential therapeutics fail in clinical trials and both disease progression and resistance call for combination therapy with several drugs, the identification of additional classes of inhibitory molecules is essential. Using an exhaustive virtual-screening and experimental validation approach, we identify several additional small-molecule cruzain inhibitors. Further optimization of these chemical scaffolds could lead to the development of novel drugs useful in the treatment of Chagas' disease.     

Detection and treatment of Trypanosoma cruzi: a patent review (2011-2015)

Introduction: Trypanosoma cruzi is the etiologic agent of American trypanosomiasis (Chagas disease), which is one of the important parasitic diseases worldwide. The number of infected people with T. cruzi diminished from 18 million in 1991 to 6 million in 2010, but it is still the most prevalent parasitic disease in the Americas. The existing chemotherapy is still deficient and based on two drugs: nifurtimox and benznidazole, which are not FDA-approved in the United States.

Areas covered: This review covers the current and future directions of Chagas disease chemotherapy based on drugs that interfere with relevant metabolic pathways. This article also illustrates the challenges of diagnosis, which in recent infections, is only detected when the parasitemia is high (direct detection); whereas, in the chronic phase is reached after multiple serological tests.

Expert opinion: The current chemotherapy is associated with long term treatments and severe side effects. Nifurtimox and benznidazole are able to cure at least 50% of recent infections. Nevertheless, they suffer from major drawbacks: selective drug sensitivity on different T. cruzi strains and serious side effects. The aim of this review is focused on presenting an up-to-date status of the chemotherapy and diagnosis.     

Synthesis of 2-hydrazolyl-4-thiazolidinones based on multicomponent reactions and biological evaluation against Trypanosoma Cruzi

A series of 18 novel 2-hydrazolyl-4-thiazolidinones-5-carboxylic acids, amides and 5,6-α,β-unsaturated esters were synthesized, and their in vitro activity on cruzipain and T. cruzi epimastigotes was determined. Some agents show activity at 37 μm concentration in the enzyme assay. Computational tools and docking were used to correlate the biological response with the physicochemical parameters of the compounds and their cruzipain inhibitory effects.     

Novel agents derived from the currently approved treatments for MM: novel proteasome inhibitors and novel IMIDs

Introduction: Several novel proteasome inhibitors (PIs) and immunomodulatory agents (IMIDs) with similar, but not exactly the same, mechanisms of action than their predecessors have been developed in the last years with three different aims: to increase the efficacy; to overcome the resistance and to exhibit a better toxicity profile.

Areas covered: This review summarizes the mechanism of action of novel PIs (carfilzomib, ONX-0912, MLN-9708, marizomib and CEP-18770) and IMIDs (pomalidomide), stressing the similarities and differences with their parental drugs. It also reviews their most updated clinical results. A search of the recent literature in published papers and abstracts from the most important oncology scientific meetings (ASCO and ASH) has been performed.

Expert opinion: Novel PIs and IMIDs show clinical activity as single agents and in combination with dexamethasone, with similar or even higher efficacy than their predecessors; moreover, they may even overcome resistance to their parental drugs, indicating that there are some differences in their mechanisms of action and resistance. The investigation of these mechanisms of resistance and ways to overcome it would allow the optimization of the sequential use of these agents, and the design of novel therapeutic strategies and more appropriate scientifically based combinations.     

Novel approaches for preventing acute graft-versus-host disease after allogeneic hematopoietic stem cell transplantation

Introduction: Allogeneic hematopoietic stem cell transplantation (alloHSCT) offers potential curative treatment for a wide range of malignant and nonmalignant hematological disorders. However, its success may be limited by post-transplant acute graft-versus-host disease (aGVHD), a systemic syndrome in which donor’s immune cells attack healthy tissues in the immunocompromised host. aGVHD is one of the main causes of morbidity and mortality after alloHSCT. Despite standard GVHD prophylaxis regimens, aGVHD still develops in approximately 40–60% of alloHSCT recipients.

Areas covered: In this review, after a brief summary of current knowledge on the pathogenesis of aGVHD, the authors review the current combination of a calcineurin inhibitor with an antimetabolite with or without added anti-thymocyte globulin (ATG) and emerging strategies for GVHD prevention.

Expert opinion: A new understanding of the involvement of cytokines, intracellular signaling pathways, epigenetics and immunoregulatory cells in GVHD pathogenesis will lead to new standards for aGVHD prophylaxis allowing better prevention of severe aGVHD without affecting graft-versus-tumor effects.