New Chemotherapeutic Strategies Against Malaria, Leishmaniasis and Trypanosomiases

Abstract

Due to the persistent lack of suitable vaccines, chemotherapy remains the only option for the treatment of patients infected by protozoan parasites. However, most available antiparasitic drugs have serious disadvantages, ranging from high cost and poor compliance to high toxicity and rapid induction of resistance. In recent decades basic research laboratories identified a considerable number of promising new molecules, but their development has not been pursued in depth by pharmaceutical firms because of poor prospects of economic return. The establishment of adequately funded public-private partnerships is currently reversing the trend. This review deals with new drugs against Plasmodium, Leishmania and Trypanosoma parasites, focusing on the molecules that are in the most advanced stage of development. The purpose of this article is to provide the reader with a panoramic view of the updated literature on the challenges and strategies of contemporary antiprotozoal drug research, paying the due attention to the already published reviews.Keywords: Antibiotics, antiprotozoal chemotherapy, Leishmania, natural products, Plasmodium, Trypanosoma. 4 INTRODUCTIONInfections caused by parasitic protozoa take an enormous toll on human health. Their prevalence is higher in tropical and equatorial countries, where the major number of deaths is due to malaria, leishmaniasis, and African and American trypanosomiasis. High mortality rates are associated to poor sanitary conditions, high percentages of untreated HIV-infected individuals, and lack of efficient prophylactic measures [1]. In the developed countries the situation is not so tragic, but nonetheless it has its drawbacks. If it is true that in these countries most HIV-infected patients are treated, the number of chronically immuno-deficient carriers of transplanted organs is set to grow. In these patients latent parasitic infections, such as leishmaniasis and toxoplasmosis, can reappear as opportunistic infections. Moreover, the climate changes linked to global warming in temperate countries are extending the insect vector habitats, as is the case of the northward spread of leishmania-transmitting sandflies, assessed by epidemiological surveys of canine leishmaniasis in Italy [2][3][4]. Some additional cases of parasitic infections have also been registered due to "transplant tourism", i.e. travel with the intent of receiving or donating an organ, a practice that is rapidly increasing [5]. A further danger for industrialized countries comes from massive migration of infected subjects from endemic countries: a typical example is the presence of thousands of Trypanosoma cruzi-infected people in North America and Spain [6].In the absence of prophylactic or curative vaccines the only available choice is chemotherapy. However, this relies on drugs which are tens of years old, afflicted with serious disadvantages, such as heavy side-effects, selection of resistant strains, or high production costs. Unfortunately, this situation is not likely to improve in the short t...

Essential Oil from Piper aduncum: Chemical Analysis, Antimicrobial Assessment, and Literature Review

“…Leishmaniasis exhibits a range of clinical appearances including cutaneous (CL), mucocutaneous (MCL), and visceral (VL) forms. In these human pathogenic trypanosomes, the management of the infections is currently based on chemotherapeutics that are not ideal due to cost, availability, toxicity, and resistance [ 39 ].…”

“…The first phase is characterized by nonspecific clinical symptoms, and trypanosomes are restricted to the lymphatic and circulatory systems, whereas in the second stage severe neurological symptoms appear, and parasites can be found in the brain and in cerebrospinal fluid [ 40 ]. It has been estimated that 60 million people in sub-Saharan Africa countries are currently at risk, and around 50,000 to 70,000 people are infected [ 39 ]. Chagas disease is present in Central and South America, with an annual death toll of about 50,000 people in 18 endemic countries, while more than 8 million people are infected, while nearly 90 million people are at risk of infection [ 41 ].…”

“…showed variable susceptibilities to P. aduncum EO, with the species that cause visceral leishmaniasis ( L. infantum and L. donovani ) showing lower IC 50 values. In the clinical form of VL, the parasites colonize the bone marrow, liver, and spleen, resulting in host immunosuppression and death in the absence of treatment [ 39 ]. Finally, the species that causes CL ( L. amazonensis ), in which parasites remain localized in the epithelial tissues, the EO displayed a higher IC 50 value.…”

Multicomponent reaction-based synthesis and biological evaluation of tricyclic heterofused quinolines with multi-trypanosomatid activity

“…These diseases are usually confined to rural areas of endemic countries (sub-Saharan Africa for HAT, mainly Central and South America for Chagas disease, and Middle East and Asia, East Africa, Central and South America and Southern Europe for leishmaniasis). However, climate changes due to global warming, which may result in an extension of the insect vector habitats, as well as international travel and immigration patterns may expand the geographical impact of these infectious diseases, thereby increasing the population at risk [5] . Travel to and immigration from endemic countries have made Chagas disease and several forms of leishmaniasis emerging infections in the United States (both infections), and Spain and Japan (Chagas disease) [6] , [7] .…”

“…In the absence of preventive or therapeutic vaccines and rigorous control of insect vectors [5] , [14] , the development of novel chemotherapies against these infectious diseases, with appropriate efficacy and safety profiles, is desperately needed [15] , [16] . Besides combinations of approved antiprotozoan drugs or repurposing of known drugs with other indications [8] , [14] , [15] , increasing research efforts are being made to design novel chemical entities that hit one or several biological targets which play a key role in the biology of the parasite and are sufficiently different from those in the mammalian host cells as to enable selective toxicity [5] , [9] , [17] , [18] , [19] , [20] , [21] , [22] , [23] . However, while we are gaining a better understanding of the relevant parasite targets, phenotypic whole cell screening of novel compounds or chemical libraries remains a very successful approach for anti-protozoan drug discovery [8] , [24] , [25] .…”