Antileishmanial Activities of Rhodacyanine Dyes
TL;DR: Rhodacyanine dyes, potent antimalarial agents, was found to possess strong antileishmanial activity against Leishmania major in vitro.
Abstract: Rhodacyanine dyes, potent antimalarial agents, was found to possess strong antileishmanial activity against Leishmania major in vitro. The efficacies of several compounds are comparable to one of clinically used amphotericin B.
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TL;DR: The disease history and parasite biology is described followed by a summary of the currently available treatments and, finally, review reports of novel small molecules with antileishmanial activity.
Abstract: Leishmaniasis is a parasitic disease that presents four main clinical syndromes: cutaneous leishmaniasis (CL), mucocutaneous leishmaniasis (MCL), visceral leishmaniasis/kala azar (VL), and post kala azar dermal leishmaniasis (PKDL). Causative Leishmania are protozoan parasites that are transmitted among mammalian hosts by phlebotomine sandflies. In mammalian hosts, parasite cells proliferate inside the host phagocytic cells as round amastigotes. Infection of sandflies with Leishmania occurs during insect feeding on infected mammalian hosts. After introduction into the insect gut together with the blood meal, Leishmania amastigotes transform into elongated flagellated promastigotes that propagate in the insect gut. A new round of infection is initiated after the infected sandfly takes a blood meal from a naive mammalian host and introduces Leishmania parasites into the bite wound in the host dermis (Scheme 1). More than 20 different Leishmania species have been found to cause human leishmaniasis (Table 1).
Leishmaniasis is endemic in 98 countries and is closely associated with poverty. More than a million new cases are reported per year and 350 million people are at risk of contracting the infection. For the most severe form of leishmaniasis, VL, ∼300 000 new cases are estimated to occur annually resulting in ∼40 000 deaths. Approximately 90% of all VL cases occur in 3 endemic foci: 1. India, Bangladesh, and Nepal; 2. East Africa; and 3. Brazil. In spite of the high prevalence, currently available treatments for leishmaniasis are inadequate. Pentavalent antimonials, the standard treatment for leishmaniasis for many decades, are not efficacious in Bihar (∼60% of VL cases worldwide) any longer due to widespread resistance to the drug in this region. Several new VL treatments have emerged during the past 10–15 years, but each has serious shortcomings (summarized in Table 2). These include paromomycin (injectable, long treatment, region-dependent efficacy), miltefosine (cost, teratogenicity, long treatment), and liposomal amphotericin B (cost, hospitalization, region-dependent efficacy). An additional challenge is represented by patients with HIV/VL coinfections who are more difficult to cure (lower initial and final cure rates), have greater susceptibility to drug toxicity, and have higher rates of death and relapse.
Due to the limitations of the existing treatments, better drugs are urgently needed. Ideally, new VL drugs would be efficacious across all endemic regions, would affect cure in ≤10 days, and would cost <$10 per course (for a complete target product profile for new VL drugs, which was formulated by DNDi, see Table 4).1 Here we describe the disease history and parasite biology followed by a summary of the currently available treatments and, finally, review reports of novel small molecules with antileishmanial activity.
267 citations
TL;DR: The novel [ 0,0,0]-rhodacynines, 3e and 3h, possessing a benzothiazole moiety, were shown to have highly promising antimalarial activities in vivo and were found to be orally bioavailable.
49 citations
TL;DR: Quarternary carbolinium cations showed much higher potencies in vitro than electronically neutral beta-carbolines and a good correlation was observed between pi-delocalized lipophilic cationic (DLC) structure and antimalarial efficacy.
Abstract: Several β-carbolines including naturally occurring substances and their corresponding cationic derivatives were synthesized and evaluated for antimalarial (antiplasmodial) activity in vitro and in vivo. A tetracyclic carbolinium salt was elucidated for antileishmanial and antitrypanosomal activities in vitro as well as antiplasmodial activity. Quarternary carbolinium cations showed much higher potencies in vitro than electronically neutral β-carbolines and a good correlation was observed between π-delocalized lipophilic cationic (DLC) structure and antimalarial efficacy. β-Carbolinium compounds exhibit medium suppressive activity in vivo against rodent malaria.
47 citations
TL;DR: There is an urgent need to find new ways of funding research for leishmaniasis drugs, incentivizing product development partnerships and pushing forward innovation.
Abstract: Introduction: Although leishmaniasis is estimated to cause the ninth largest disease burden among individual infectious diseases, it is still one of the most neglected diseases in terms of drug development. Current drugs are highly toxic, resistance is common and compliance of patients to treatment is low, as treatment is long and drug price is high.Areas covered: In this review, the authors carried out a patent landscape in search for new perspectives for leishmaniasis therapy. This search encompassed patent documents having priority date between 1994 and 2014. Selected compounds were compared to current anti-leishmanial drugs regarding efficacy and toxicity, when experimental data were available.Expert opinion: Most patents related to drugs for leishmaniasis have not been produced by the pharmaceutical industry but rather by public research institutes or by universities, and the majority of the inventions disclosed are still in preclinical phase. There is an urgent need to find new ways of funding resea...
33 citations
Cites background from "Antileishmanial Activities of Rhoda..."
...major inhibitory activity than standard drug miltefosine and lower cytotoxicity than an allosteric Hsp70 inhibitor compound with anti-Leishmania activity, the rhodacyanine dye MKT-077 [86,87], demonstrating effective anti-Leishmania activity with potentially less side effects [88]....
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...The in vitro data showed that the synthesized rhodacyanine derivatives exhibited far higher L. major inhibitory activity than standard drug miltefosine and lower cytotoxicity than an allosteric Hsp70 inhibitor compound with anti-Leishmania activity, the rhodacyanine dye MKT-077 [86,87], demonstrating effective anti-Leishmania activity with potentially less side effects [88]....
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TL;DR: Benzothiazole cyanine compounds (PubChem 16196319 and 16196223) displayed potent activity against intracellular amastigotes, prompting a search for commercially available compounds that were structurally related.
Abstract: A previous screen of ∼200,000 compounds from the PubChem database identified 70 compounds possessing 50% effective concentrations (EC 50 s) below 1 μM against Leishmania major promastigotes that were not toxic to mammalian epithelial cancer cells at this concentration (E. Sharlow et al., PLoS Negl. Trop. Dis. 3:e540, 2009). Based on availability and chemical exclusion criteria, 31 of these compounds were purchased from commercial suppliers and evaluated for in vitro activity against intracellular L. donovani and L. amazonensis parasites. Benzothiazole cyanine compounds (PubChem 16196319 and 16196223) displayed potent activity against intracellular amastigotes, prompting a search for commercially available compounds that were structurally related. Pubchem 123859 (the cyanine dye thiazole orange) showed exceptionally potent activity against intracellular L. donovani in vitro (50% inhibitory concentration [IC 50 ] = 21 ± 12 nM) and low cytotoxicity against Vero cells (IC 50 = 7,800 ± 200 nM). Administration of 123859 and 16196319 at a dose of 1 mg/kg of body weight intraperitoneally (i.p.) daily for 5 days resulted in 44% ± 4% and 42% ± 3% suppression of liver parasitemia in L. donovani-infected BALB/c mice, respectively, compared to the untreated control group (the reductions in liver parasitemia were 30% ± 5% and 27% ± 4%, respectively, compared to the (2-hydroxypropyl)-β-cyclodextrin solution (HPβCD) vehicle control, which itself displayed some antileishmanial activity). Benzothiazole-containing cyanine dyes are thus potential lead compounds for the discovery of novel antileishmanial agents.
25 citations
Cites background from "Antileishmanial Activities of Rhoda..."
...It has been speculated that the antileishmanial rhodacyanines may disrupt parasite membrane potential (36, 45), although no supporting data were given....
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...Only one cyanine compound lacking the rhodanine ring similar to those reported in our study, 1-methyl-2-[(3-methyl-1,3benzothiazol-2(3H)-ylidene)methyl]pyridinium tosylate, was included in these papers (34, 36)....
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