Imidazolopiperazines:  Hit to Lead Optimization of New Antimalarial Agents

Wu, Tao; Nagle, A. S.; Kuhen, Kelli; Gagaring, Kerstin; Borboa, Rachel; Francek, Caroline; Chen, Zhong; Plouffe, David; Goh, Anne; Lakshminarayana, Suresh B.; Wu, Jeanette; Ang, Hui Qing; Zeng, Peiting; Kang, Min Low; Tan, Wei; Tan, Maria Carmen S.; Ye, Nicole; Lin, Xuena; Caldwell, Christopher; Ek, Jared; Skolnik, Suzanne; Li, Fenghua; Wang, Jianling; Chang, Jonathan; Li, Chun; Hollenbeck, Thomas; Tuntland, Tove; Isbell, John; Fischli, Christoph; Brun, Reto; Rottmann, Matthias; Dartois, Véronique; Keller, Thomas H.; Diagana, Thierry T.; Winzeler, Elizabeth A.; Glynne, Richard; Tully, David C.; Chatterjee, Arnab K.

doi:10.1021/jm2003359

Cited by 91 publications

(90 citation statements)

References 25 publications

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“…The ozonide OZ439, 11 the aminopyridine MMV390048, 12 and the spiroindolone NITD609 13 all effectively clear asexual, blood-stage parasites in mouse models of malaria with a single oral dose and also inhibit gametocyte development, which reduces the potential for malaria transmission. In contrast, several imidazolopiperazines, 14,15 8-aminoquinolines, 16 and antirespiratory compounds 17,18 have been identified as single-dose causal prophylactics, which inhibit the sporozoite and liverstage parasites that are responsible for the earliest stages of Plasmodium infection. Although each of these antimalarials is highly potent at specific stages of the parasite life cycle, it has not yet been possible for a single agent to provide simultaneous cures for blood, liver, and transmissive stage malaria after a single oral dose.…”

Section: Introductionmentioning

confidence: 99%

Inhibition of Cytochrome bc1 as a Strategy for Single-Dose, Multi-Stage Antimalarial Therapy

Stickles

Ting

Morrisey

et al. 2015

The American Society of Tropical Medicine and Hygiene

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Abstract. Single-dose therapies for malaria have been proposed as a way to reduce the cost and increase the effectiveness of antimalarial treatment. However, no compound to date has shown single-dose activity against both the bloodstage Plasmodium parasites that cause disease and the liver-stage parasites that initiate malaria infection. Here, we describe a subset of cytochrome bc 1 (cyt bc 1 ) inhibitors, including the novel 4(1H)-quinolone ELQ-400, with single-dose activity against liver, blood, and transmission-stage parasites in mouse models of malaria. Although cyt bc 1 inhibitors are generally classified as slow-onset antimalarials, we found that a single dose of ELQ-400 rapidly induced stasis in blood-stage parasites, which was associated with a rapid reduction in parasitemia in vivo. ELQ-400 also exhibited a low propensity for drug resistance and was active against atovaquone-resistant P. falciparum strains with point mutations in cyt bc 1 . Ultimately, ELQ-400 shows that cyt bc 1 inhibitors can function as single-dose, blood-stage antimalarials and is the first compound to provide combined treatment, prophylaxis, and transmission blocking activity for malaria after a single oral administration. This remarkable multi-stage efficacy suggests that metabolic therapies, including cyt bc 1 inhibitors, may be valuable additions to the collection of single-dose antimalarials in current development.

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Section: Introductionmentioning

confidence: 99%

Inhibition of Cytochrome bc1 as a Strategy for Single-Dose, Multi-Stage Antimalarial Therapy

Stickles

Ting

Morrisey

et al. 2015

The American Society of Tropical Medicine and Hygiene

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“…Dada su plasticidad química, los compuestos sintéticos de tipo imidazolpiperazina proporcionan una base estructural para el desarrollo de medicamentos en general y como antipalúdicos, ya que su estructura química no se relaciona con ningún medicamento antimalárico actual, lo que representa una ventaja porque evita la resistencia cruzada (38).…”

Section: Discussionunclassified

Avances en la búsqueda y desarrollo de quimioprofilácticos causales para malaria

Ríos-Orrego

Trujillo

Pabón-Vidal

2017

iatreia

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RESUMENLa malaria es una enfermedad infecciosa de importancia epidemiológica mundial, producida por diferentes especies del género Plasmodium. La quimioprofilaxis causal (QC) evita la infección y/o el desarrollo de las formas hepáticas de Plasmodium spp. Considerando recientemente la QC como una estrategia para reducir la carga de morbimortalidad en regiones endémicas para malaria, en el marco de programas para el control, la eliminación o la posible erradicación de la enfermedad, se hizo una revisión no sistemática de la literatura para conocer el estado del avance de las investigaciones sobre quimioprofilácticos causales en modelos in vivo para malaria, para aportar al conocimiento, presentando un panorama actualizado sobre el tema, y llamar la atención acerca de la importancia y la necesidad de nuevos medicamentos con efecto quimioprofiláctico. Para ello, se consultaron las bases de datos: PubMed, ScienceDirect, Google Scholar y la página oficial de la Organización Mundial de la Salud (OMS), combinando los descriptores o palabras clave: chemoprophylaxis, quimioprofilaxis, malaria, Plasmodium e in vivo. Luego de revisar 33 artículos de la literatura mundial y 4 informes de la OMS, publicados entre los años 1995 y 2015, se concluye que la molécula semisintética NCP-tazopsina y las moléculas sintéticas: KAF156 (imidazolpiperazina) y tafenoquina (8 aminoquinolina), son los agentes QC más promisorios en el momento. Estas moléculas pueden convertirse en una alternativa para el control de la malaria en un futuro cercano.

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“…This imidazolopiperazine seems to inhibit neither protein biosynthesis nor cytochrome b c 1, but arrests the parasite in its early stages of development 61,62 .…”

Section: [Genz-668764]mentioning

confidence: 97%

Recent advances in novel heterocyclic scaffolds for the treatment of drug-resistant malaria

Kumar

Singh

Patial

et al. 2015

Journal of Enzyme Inhibition and Medicinal Chemistry

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Malaria is a major public health problem all over the world, particularly in tropical and subtropical countries due to the development of resistance and most deadly infection is caused by Plasmodium falciparum. There is a direct need for the discovery of new drugs with unique structures and mechanism of action to treat sensitive and drug-resistant strains of various plasmodia for radical cure of this disease. Traditional compounds such as quinine and related derivatives represent a major source for the development of new drugs. This review presents recent modifications of 4-aminoquinoline and 8-aminoquinolone rings as leads to novel active molecules which are under clinical trials. The review also encompasses the other heterocyclic compounds emerged as potential antimalarial agents with promising results such as acridinediones and acridinone analogues, pyridines and quinolones as antimalarials. Miscellaneous heterocyclics such as tetroxane derivatives, indole derivatives, imidazolopiperazine derivatives, biscationic choline-based compounds and polymer-linked combined antimalarial drugs are also discussed. At last brief introduction to heterocyclics in natural products is also reviewed. Most of them have been under clinical trials and found to be promising in the treatment of drug-resistant strains of Plasmodium and others can be explored for the same purpose.

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Imidazolopiperazines: Hit to Lead Optimization of New Antimalarial Agents

Cited by 91 publications

References 25 publications

Inhibition of Cytochrome bc1 as a Strategy for Single-Dose, Multi-Stage Antimalarial Therapy

Inhibition of Cytochrome bc1 as a Strategy for Single-Dose, Multi-Stage Antimalarial Therapy

Avances en la búsqueda y desarrollo de quimioprofilácticos causales para malaria

Recent advances in novel heterocyclic scaffolds for the treatment of drug-resistant malaria

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