H
H. label and by trypan blue exclusion assessments with macrophages, which showed that this IC50s against the host cells were 4 to 5 orders of magnitude greater that those against the intracellular parasites. Taken together, our results show that ER-119884 and E5700 are unusually potent and selective inhibitors of the growth of with three different clinical forms, LGX 818 (Encorafenib) visceral, cutaneous, and mucocutaneous. It is associated with significant rates of morbidity and mortality in many countries around the world and affects ca. 15 million people (21, 30, 53). is the species responsible for cutaneous leishmaniasis in South LGX 818 (Encorafenib) America, where the lesions are confined to the skin. However, in some individuals, infections can develop into diffuse leishmaniasis when the patient’s immune system fails to react LGX 818 (Encorafenib) against the parasite (30), and it has also been reported that this parasite can cause visceral or post-kala-azar dermal leishmaniasis (1). Currently, the mainstay of the chemotherapy employed for the treatment of visceral and cutaneous/mucocutaneous leishmaniasis in Brazil remains pentavalent antimonials, such as pentostam and glucantime, which are very unsatisfactory due to their frequent toxic effects and the growing rates of resistance to the drugs in several parts of the world (11). LGX 818 (Encorafenib) Secondary treatments include pentamidine and amphotericin B, which are mainly employed in resistant cases when the antimonials fail (10). For visceral leishmaniasis, miltefosine (Impavido) has successfully been employed by the oral route in India (42), but a WHO statement indicates that it is teratogenic and has a thin chemotherapeutic windows (17). Paromomycin and liposomal amphotericin B are other brokers that may possibly be used against visceral leishmaniasis, and they are currently used to treat Indian patients living in regions where the resistance of the parasite to antimonials is KRAS usually widespread. On the other hand, for cutaneous leishmaniasis, new alternatives such as short courses of antimonial, topical paromomycin, and oral miltefosine have been developed; however, those studies are in progress in areas of endemicity, such as Guatemala and Colombia, and inconsistent results are being obtained between the different regions (3). Thus, there is a great necessity to develop new drugs that are efficacious, safe, and more accessible. Several studies have shown that this ergosterol biosynthesis pathway is usually a promising target in the development of a rational chemotherapeutic strategy against and other trypanosomatids, because ergosterol is essential for the parasite’s viability and is absent in mammalian cells (36, 47). Different classes of ergosterol biosynthesis inhibitors have been shown to be active against trypanosomatid parasites (4, 6, 9, 19, 23-27, 29, 35-39, 41, 45-49, 51, 52). One important enzyme of the sterol biosynthesis pathway is usually squalene synthase (SQS), which catalyzes the head-to-head condensation of two molecules of farnesyl pyrophosphate (FPP) to produce squalene (2). This is the first committed step in the sterol pathway, and its inhibition does not impact the biosynthesis of other essential isoprenoids (18). SQS has been under intense scrutiny with the aim of developing new cholesterol-lowering brokers for humans. Previous work has exhibited the effect of quinuclidine-based SQS inhibitors as cholesterol- and triglyceride-lowering brokers in experimental studies with animals (5, 7, 33). On the other hand, LGX 818 (Encorafenib) several reports have explained the potent and selective activity of the same class of compounds against parasites such as (4, 6, 9, 26, 32, 39, 41, 48, 49). ER-119884 and E5700 (Fig. ?(Fig.1),1), two novel quinuclidine-based SQS inhibitors developed by Eisai Co. (Tokyo, Japan) as cholesterol- and triglyceride-lowering brokers in humans, have recently been shown to be potent anti-agents in vitro and in vivo, and their activities have been shown to be associated with a dramatic depletion of the parasite’s endogenous sterols (48). In vivo studies with a murine model of acute Chagas’ disease indicated that E5700 is able to provide full protection against death and to completely suppress the parasitemia, with no toxicity to the host (48). That study indicated that ER-119884 and E5700 potentially have activity against trypanosomatid parasites. On the other hand, these compounds were also active against (4) and (39) cells; those studies showed that this inhibitor induces ultrastructural alterations in several subcellular organelles, including plasma and flagellar membranes, the endoplasmic reticulum,.