Inhibition by Dications of In Vitro Growth of Leishmania major and Leishmania tropica: Causative Agents of Old World Cutaneous Leishmaniasis

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195

Chagas' disease, a neglected tropical illness for which current therapy is unsatisfactory, is caused by the intracellular parasite Trypanosoma cruzi. The goal of this work is to investigate the in vitro and in vivo effects of the arylimidamide (AIA) DB766 against T. cruzi. This arylimidamide exhibits strong trypanocidal activity and excellent selectivity for bloodstream trypomastigotes and intracellular amastigotes (Y strain), giving IC 50 s (drug concentrations that reduce 50% of the number of the treated parasites) of 60 and 25 nM, respectively. DB766 also exerts striking effects upon different parasite stocks, including those naturally resistant to benznidazole, and displays higher activity in vitro than the reference drugs. By fluorescent and transmission electron microscopy analyses, we found that this AIA localizes in DNA-enriched compartments and induces considerable damage to the mitochondria. DB766 effectively reduces the parasite load in the blood and cardiac tissue and presents efficacy similar to that of benznidazole in mouse models of T. cruzi infection employing the Y and Colombian strains, using oral and intraperitoneal doses of up to 100 mg/kg/day that were given after the establishment of parasite infection. This AIA ameliorates electrocardiographic alterations, reduces hepatic and heart lesions induced by the infection, and provides 90 to 100% protection against mortality, which is similar to that provided by benznidazole. Our data clearly show the trypanocidal efficacy of DB766, suggesting that this AIA may represent a new lead compound candidate to Chagas' disease treatment.

Section: Discussionsupporting

confidence: 55%

Arylimidamide DB766, a Potential Chemotherapeutic Candidate for Chagas' Disease Treatment

Batista

Oliveira

et al. 2010

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195

“…Numerous dicationic compounds have been tested as antileishmanial drugs over the past few years (3)(4)(5)(6). In this work, we determined the antileishmanial effect of a set of human choline kinase inhibitors with a bis-pyridinium-type structure (see Table S1 in the supplemental material) and provide a first insight into the antileishmanial mechanism of action of a promising lead compound.…”

Section: Discussionmentioning

confidence: 99%

“…Pentamidine is actively transported into Leishmania promastigotes (1) and binds to nuclear and mitochondrial DNA (kinetoplasts), thereby hindering replication and transcription at the mitochondrial level (2). New diamidine and choline derivate dications have been developed recently in order to find new drugs with improved activity against leishmaniasis and lower toxicity (3)(4)(5)(6).…”

mentioning

confidence: 99%

4-Amino Bis-Pyridinium Derivatives as Novel Antileishmanial Agents

Gómez-Pérez

Manzano

García-Hernández

et al. 2014

The antileishmanial activity of a series of bis-pyridinium derivatives that are analogues of pentamidine have been investigated, and all compounds assayed were found to display activity against promastigotes and intracellular amastigotes of Leishmania donovani and Leishmania major, with 50% effective concentrations (EC 50 s) lower than 1 M in most cases. The majority of compounds showed similar behavior in both Leishmania species, being slightly more active against L. major amastigotes. However, compound VGP-106 {1,1=-(biphenyl-4,4=-diylmethylene)bis[4-(4-bromo-N-methylanilino)pyridinium] dibromide} exhibited significantly higher activity against L. donovani amastigotes (EC 50 , 0.86 ؎ 0.46 M) with a lower toxicity in THP-1 cells (EC 50 , 206.54 ؎ 9.89 M). As such, VGP-106 was chosen as a representative compound to further elucidate the mode of action of this family of inhibitors in promastigote forms of L. donovani. We have determined that uptake of VGP-106 in Leishmania is a temperature-independent process, suggesting that the compound crosses the parasite membrane by diffusion. Transmission electron microscopy analysis showed a severe mitochondrial swelling in parasites treated with compound VGP-106, which induces hyperpolarization of the mitochondrial membrane potential and a significant decrease of intracellular free ATP levels due to the inhibition of ATP synthesis. Additionally, we have confirmed that VGP-106 induces mitochondrial ROS production and an increase in intracellular Ca 2؉ levels. All these molecular events can activate the apoptotic process in Leishmania; however, propidium iodide assays gave no indication of DNA fragmentation. These results underline the potency of compound VGP-106, which may represent a new avenue for the development of novel antileishmanial compounds.

“…In our efforts to identify promising antiprotozoal agents from a library of aromatic diamidines and their analogues, we have identified a new class of molecules, arylimidamides (AIAs; previously referred to as "reversed" amidines [26,27]), that exhibited submicromolar 50% inhibitory concentrations (IC 50 s) in the axenic Leishmania donovani amastigote assay and the L. donovani-infected macrophage assay (26) and nanomolar IC 50 s in Leishmania promastigote assays (22,23). In addition, AIAs demonstrated submicromolar IC 50 s against Trypanosoma cruzi parasites (19,24,26), the causative agent for the devastating Chagas' disease (or human American trypanosomiasis, also a neglected tropical disease).…”

mentioning

confidence: 99%

Novel Arylimidamides for Treatment of Visceral Leishmaniasis

Wang

Zhu

Srivastava

et al. 2010

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111

Arylimidamides (AIAs) represent a new class of molecules that exhibit potent antileishmanial activity (50% inhibitory concentration [IC 50 ], <1 M) against both Leishmania donovani axenic amastigotes and intracellular Leishmania, the causative agent for human visceral leishmaniasis (VL). A systematic lead discovery program was employed to characterize in vitro and in vivo antileishmanial activities, pharmacokinetics, mutagenicities, and toxicities of two novel AIAs, DB745 and DB766. They were exceptionally active (IC 50 < 0.12 M) against intracellular L. donovani, Leishmania amazonensis, and Leishmania major and did not exhibit mutagenicity in an Ames screen. DB745 and DB766, given orally, produced a dose-dependent inhibition of liver parasitemia in two efficacy models, L. donovani-infected mice and hamsters. Most notably, DB766 (100 mg/kg of body weight/day for 5 days) reduced liver parasitemia in mice and hamsters by 71% and 89%, respectively. Marked reduction of parasitemia in the spleen (79%) and bone marrow (92%) of hamsters was also observed. Furthermore, these compounds distributed to target tissues (liver and spleen) and had a moderate oral bioavailability (up to 25%), a large volume of distribution, and an elimination half-life ranging from 1 to 2 days in mice. In a repeat-dose toxicity study of mice, there was no indication of liver or kidney toxicity for DB766 from serum chemistries, although mild hepatic cell eosinophilia, hypertrophy, and fatty changes were noted. These results demonstrated that arylimidamides are a promising class of molecules that possess good antileishmanial activity and desirable pharmacokinetics and should be considered for further preclinical development as an oral treatment for VL.Leishmaniasis, a neglected tropical disease, is caused by parasitic protozoa of the genus Leishmania, including 20 species that are pathogenic for humans (21). Clinical manifestations of leishmaniasis mainly consist of cutaneous, mucocutaneous, visceral, and post-kala-azar dermal leishmaniasis, with symptoms ranging from skin and mucosal ulceration to systemic infection that is fatal if left untreated (6). An estimated 12 million people are currently infected with Leishmania, and up to 350 million people in 88 countries are at risk of infection (35). Approximately 2 million new cases of leishmaniasis are believed to occur annually, with 1.5 million for cutaneous leishmaniasis and 0.5 million for visceral leishmaniasis (VL). In macrophages, Leishmania amastigotes adapt to thrive in an acidic subcellular compartment, the parasitophorous vacuole (PV; pH ϳ5) (2), where they maintain a neutral intracellular pH within the parasite by an energy-dependent process (9). Multiple layers of membrane barriers (i.e., host macrophage plasma membrane, phagolysosomal membrane, and Leishmania amastigote plasma membrane) presumably present a formidable challenge for chemotherapeutic agents to target Leishmania parasites in mammalian hosts.Current chemotherapies for leishmaniasis have many limitations, including resis...