Potent antimalarial 4-pyridones with improved physico-chemical properties

Bueno, José María; Manzano, Pilar; García, María C.; Chicharro, Jesús; Puente, Margarita; Lorenzo, Milagros; García, Adolfo; Ferrer, Santiago; Gómez, Rubén; Fraile, M. Teresa; Lavandera, José Luís; Fiandor, José M.; Vidal, Jaume; Herreros, Esperanza; Gargallo-Viola, Domingo

doi:10.1016/j.bmcl.2011.07.044

Cited by 35 publications

(30 citation statements)

References 19 publications

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“…As noted, it has been generally accepted that the 4(1H)-pyridone class, e.g., GW844520, targets the Q o oxidation site of the bc 1 complex, via analogy with the mechanism of action of the Q o targeted antimalarial atovaquone, and indeed models of the pyridone/bc 1 Q o interaction of these molecules have been previously described (33). The next generation bc 1 inhibitor quinolone, ELQ 300, was designed by replacement of the pyridone unit of GW844520, with a quinolone group as shown (Fig.…”

Section: Discussionmentioning

confidence: 96%

“…Work on improving the clinically promising 4(1H)-pyridones so far has lacked structural information (33,34). The elucidation of 4(1H)-pyridone binding within the Q i site of mitochondrial cytochrome bc 1 complex provides for the first time to our knowledge an opportunity for rational drug design to increase selectivity against Plasmodia parasites toward novel treatments and reducing transmission.…”

Section: Discussionmentioning

confidence: 99%

“…Many different classes of compound have been investigated as potential drugs and much work has focused on inhibition of the Q o site (23,(29)(30)(31)(32). The 4(1H)-pyridones have been researched for their antimalarial properties since the 1960s, based on the compound clopidol (33,34) (Fig. 1).…”

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confidence: 99%

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Antimalarial 4(1H)-pyridones bind to the Q _i site of cytochrome bc ₁

Capper

O’Neill

Fisher

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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Cytochrome bc 1 is a proven drug target in the prevention and treatment of malaria. The rise in drug-resistant strains of Plasmodium falciparum, the organism responsible for malaria, has generated a global effort in designing new classes of drugs. Much of the design/redesign work on overcoming this resistance has been focused on compounds that are presumed to bind the Q o site (one of two potential binding sites within cytochrome bc 1 ) using the known crystal structure of this large membrane-bound macromolecular complex via in silico modeling. Cocrystallization of the cytochrome bc 1 complex with the 4(1H)-pyridone class of inhibitors, GSK932121 and GW844520, that have been shown to be potent antimalarial agents in vivo, revealed that these inhibitors do not bind at the Q o site but bind at the Q i site. The discovery that these compounds bind at the Q i site may provide a molecular explanation for the cardiotoxicity and eventual failure of GSK932121 in phase-1 clinical trial and highlight the need for direct experimental observation of a compound bound to a target site before chemical optimization and development for clinical trials. The binding of the 4(1H)-pyridone class of inhibitors to Q i also explains the ability of this class to overcome parasite Q o -based atovaquone resistance and provides critical structural information for future design of new selective compounds with improved safety profiles. malaria | cytochrome bc 1 | drug discovery | Plasmodium falciparum | membrane protein

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Section: Discussionmentioning

confidence: 96%

Section: Discussionmentioning

confidence: 99%

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Antimalarial 4(1H)-pyridones bind to the Q _i site of cytochrome bc ₁

Capper

O’Neill

Fisher

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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“…Consequently, oral bioavailability of lead 4 was also extremely low at higher dosages (% F = 4 at a 2mg/kg dose in dogs and % F = 20 at a 10mg/kg dose in mice) mainly because of poor aqueous solubility (pH 2-12 < 0.1 μg/ml) [43]. The lack of dose linearity of 4 in the preclinical studies triggered the initiation of a back-up program at GSK with the goal to design 4(1 H )-pyridones with higher solubilities and increased bioavailabilities [44]. Introduction of a hydroxymethyl moiety at C6 yielded compound 5 (Figure 3), whose solubility at lower pHs (simulated gastric fluid (SGF) pH 1.2 = 372 mg/ml, where the nitrogen atom of the pridone ring is protonated p K a < 1.5, fed state simulated intestinal fluid (FeSSIF) pH 5.0 = 2.34 mg/ml) was significantly increased in comparison to its solubility at pH 7.4 (PBS pH 7.4 < 0.1 mg/ml).…”

Section: 4(1h)-pyridonesmentioning

confidence: 99%

4(1H)-Pyridone and 4(1H)-Quinolone Derivatives as Antimalarials with Erythrocytic, Exoerythrocytic, and Transmission Blocking Activities

Monastyrskyi¹,

Kyle²,

Manetsch³

2014

CTMC

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Infectious diseases are the second leading cause of deaths in the world with malaria being responsible for approximately the same amount of deaths as cancer in 2012. Despite the success in malaria prevention and control measures decreasing the disease mortality rate by 45% since 2000, the development of single-dose therapeutics with radical cure potential is required to completely eradicate this deadly condition. Targeting multiple stages of the malaria parasite is becoming a primary requirement for new candidates in antimalarial drug discovery and development. Recently, 4(1H)-pyridone, 4(1H)-quinolone, 1,2,3,4-tetrahydroacridone, and phenoxyethoxy-4(1H)-quinolone chemotypes have been shown to be antimalarials with blood stage activity, liver stage activity, and transmission blocking activity. Advancements in structure-activity relationship and structure-property relationship studies, biological evaluation in vitro and in vivo, as well as pharmacokinetics of the 4(1H)-pyridone and 4(1H)-quinolone chemotypes will be discussed.

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“…. Though, development of the compound was terminated by the MMV due to unexpected side effects as cardiotoxicity 51 . Further modifications of the template results into compound 86 (GSK932121) which was found to be highly potent both in vitro and against multidrug resistant strains of P. falciparum in a novel murine P. falciparum model 52,53 .…”

Section: Novel Triazolopyrimidine As Antimalarialsmentioning

confidence: 99%

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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Potent antimalarial 4-pyridones with improved physico-chemical properties

Cited by 35 publications

References 19 publications

Antimalarial 4(1H)-pyridones bind to the Q _i site of cytochrome bc ₁

Antimalarial 4(1H)-pyridones bind to the Q _i site of cytochrome bc ₁

4(1H)-Pyridone and 4(1H)-Quinolone Derivatives as Antimalarials with Erythrocytic, Exoerythrocytic, and Transmission Blocking Activities

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

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Potent antimalarial 4-pyridones with improved physico-chemical properties

Cited by 35 publications

References 19 publications

Antimalarial 4(1H)-pyridones bind to the Q i site of cytochrome bc 1

Antimalarial 4(1H)-pyridones bind to the Q i site of cytochrome bc 1

4(1H)-Pyridone and 4(1H)-Quinolone Derivatives as Antimalarials with Erythrocytic, Exoerythrocytic, and Transmission Blocking Activities

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

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Antimalarial 4(1H)-pyridones bind to the Q _i site of cytochrome bc ₁

Antimalarial 4(1H)-pyridones bind to the Q _i site of cytochrome bc ₁