Fluorinated Rhodacyanine (SJL-01) Possessing High Efficacy for Visceral Leishmaniasis (VL)

Yang, Mei; Arai, Chika; Bakar, Abu; Lu, Jun; Ge, Jian‐Feng; Pudhom, Khanitha; Takasu, Kiyosei; Kasai, Kazuki; Kaiser, Marcel; Brun, Reto; Yardley, Vanessa; Itoh, Isamu; Ihara, Masataka

doi:10.1021/jm9013086

Cited by 21 publications

(21 citation statements)

References 13 publications

(17 reference statements)

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“…In addition to the antileishmanial activity reported in the study by Sharlow et al, a series of papers have also described the antiprotozoal activity of cyanine dyes (21,22,(34)(35)(36)45). These reports mainly focused on the antimalarial effects of rhodanine-containing cyanines (rhodacyanines) and showed that these agents display nanomolar potency against Plasmodium falciparum in vitro (21,22,34,35) and good in vivo efficacy against murine P. berghei infections (21,22,35).…”

Section: Discussionmentioning

confidence: 99%

“…Presumably, this class was not pursued further because the sole cyanine compound investigated was slightly less potent in vitro against P. falciparum erythrocytestage parasites and L. major promastigotes compared to some tricyclic rhodacyanines studied. Two rhodacyanines displayed midnanomolar potencies against intracellular L. donovani, and treatment of L. donovani-infected mice with one of these rhodacyanines at a dose of 1.3 mg/kg/day ϫ 5 by the intravenous route resulted in 95% inhibition of liver parasitemia (45). In our study, cyanines 2312703, 16196319, and 16196223 all displayed midnanomolar potency against both intracellular L. donovani and intracellular L. amazonensis, while 123859 was highly active against intracellular L. donovani but less potent against intracellular L. amazonensis.…”

Section: Discussionmentioning

confidence: 99%

“…The lack of activity of benzothiazole cyanine 2308258 is difficult to rationalize at this time but could indicate that specific molecular targets for these compounds in Leishmania are not permissive for the terminal pyridine ring present in this molecule. It has been speculated that the antileishmanial rhodacyanines may disrupt parasite membrane potential (36,45), although no supporting data were given. This mechanistic hypothesis deserves further investigation in Leishmania.…”

Section: Discussionmentioning

confidence: 99%

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Identification of New Antileishmanial Leads from Hits Obtained by High-Throughput Screening

Zhu

Pandharkar

Werbovetz

2012

Antimicrob Agents Chemother

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A previous screen of ϳ200,000 compounds from the PubChem database identified 70 compounds possessing 50% effective concentrations (EC 50 s) below 1 M against Leishmania major promastigotes that were not toxic to mammalian epithelial cancer cells at this concentration (E. Combinations of existing antileishmanial drugs have also been studied. Different combinations of treatment with single-dose liposomal amphotericin B followed by short courses of miltefosine were extremely effective, with a single dose of liposomal amphotericin B at 5 mg/kg of body weight followed by a 10-day course of miltefosine resulting in a cure rate of 98% (32). This combination was evaluated together with other combinations consisting of (i) a single dose of 5 mg/kg liposomal amphotericin with a 10-day course of paromomycin and (ii) a 10-day course of both paromomycin and miltefosine, with all of these combinations providing a cure rate of 97% or greater (33). When given in a single 10 mg/kg dose, liposomal amphotericin B was shown to be highly effective against VL, producing a cure rate of 95.7% (30). Single-dose liposomal amphotericin B is proposed to play a central role in a VL elimination program in India, Nepal, and Bangladesh (12).SharlowDespite these improvements in VL treatment on the Indian subcontinent, unmet needs in leishmaniasis chemotherapy still exist. In Africa, only the antimonial drug sodium stibogluconate and liposomal amphotericin B are registered for treating VL. Antimonial compounds, which have been replaced by the drugs listed above for treating VL on the Indian subcontinent due to widespread antimonial resistance (31), have been used for many years against leishmaniasis, and their use is plagued by the long duration of therapy and by the associated side effects (15,18,23,31). Liposomal amphotericin B appears to be less effective against VL in Brazil (1) and in Africa (1, 14, 26) compared to India, and the expense of liposomal amphotericin B also limits its widespread use (9). Paromomycin is inexpensive and is thus a good candidate for VL treatment in African countries, but a 15 mg/kg/day regimen of paramomycin for 21 days was inferior to standard treatment with sodium stibogluconate (20 mg/kg

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Identification of New Antileishmanial Leads from Hits Obtained by High-Throughput Screening

Zhu

Pandharkar

Werbovetz

2012

Antimicrob Agents Chemother

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“…The plates were kept at room temperature. After 24 h, 20 µl of Alamar blue (12.5 mg of resazurin dissolved in 100 mlof distilled water) (Yang et al, 2010) was added to each of the wells. Absorbance of the resulting mixture was measured after 48 h at a wavelength of 540 and 630 nm using Enzyme Linked Immuno Sorbent Assay (ELISA) plate reader (Al-Nasiry et al, 2007).…”

Section: In Vitro Antipromastigote Assaymentioning

confidence: 99%

Screening of some pyrazole derivatives as promising antileishmanial agent

Tuha¹,

Bekhit²,

Seid³

2017

Afr. J. Pharm. Pharmacol.

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“…The uptake of the rhodacyanines in mitochondria may play a key role in inhibiting malaria diseases. 36,[56][57][58][59][60][61] The causal pathogenic parasites of NTDs, such as Trypanosoma spp. and Leishmania spp., belong to the Trypanosomatidae family in the Euglenozoa phylum.…”

Section: )mentioning

confidence: 99%

π-Delocalized Lipophilic Cations as New Candidates for Antimalarial, Antitrypanosomal and Antileishmanial Agents: Synthesis, Evaluation of Antiprotozoal Potency, and Insight into Their Action Mechanisms

Takasu

2016

CHEMICAL & PHARMACEUTICAL BULLETIN

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The search for new drugs that could treat tropical protozoan diseases, such as malaria or neglected tropical diseases (NTDs), motivates many medicinal chemists. New classes of antiprotozoal drugs that act through a novel mechanism of action must be developed. This review presents our efforts toward finding new candidate treatments for malaria, American trypanosomiasis, human African trypanosomiasis and leishmaniasis based on π-delocalized lipophilic cations (DLCs). DLCs, such as rhodacyanines, azarhodacyanines, β-carbolinium salts, and phenoxazinium salts, displayed strong antiprotozoal activities with highly selective indices. Several DLCs displayed moderate to excellent in vivo efficacies against Plasmodium berghei when administered intraperitoneally or orally. This review also discusses chemical biology approaches to understanding the mechanism of action underlying the antimalarial rhodacyanines.

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Fluorinated Rhodacyanine (SJL-01) Possessing High Efficacy for Visceral Leishmaniasis (VL)

Cited by 21 publications

References 13 publications

Identification of New Antileishmanial Leads from Hits Obtained by High-Throughput Screening

Identification of New Antileishmanial Leads from Hits Obtained by High-Throughput Screening

Screening of some pyrazole derivatives as promising antileishmanial agent

π-Delocalized Lipophilic Cations as New Candidates for Antimalarial, Antitrypanosomal and Antileishmanial Agents: Synthesis, Evaluation of Antiprotozoal Potency, and Insight into Their Action Mechanisms

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