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

Monastyrskyi, Andrii; Kyle, Dennis E.; Manetsch, Roman

doi:10.2174/1568026614666140808124638

Cited by 21 publications

(22 citation statements)

References 51 publications

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“…Quinolones are used clinically for treatmento ft uberculosis, [17] selected examples have acquired lead status as antimalarial drugs [18,19] and display potent dual target effects when combined with the appropriate drug partner. [19] The precept is that artemisinins and other peroxides behave as oxidants in the intracellularm ilieu by rapidly oxidizingr educed flavin cofactors such as FADH 2 of flavoenzyme disulfide reductases important for maintaining levels of GSH and other endogenoust hiols required for intercepting reactive oxygen species( ROS). [16] Pf as an aerobic organism experiences abnormally high oxidative stress within an erythrocyte.…”

Section: Introductionmentioning

confidence: 99%

Preliminary Evaluation of Artemisinin–Cholesterol Conjugates as Potential Drugs for the Treatment of Intractable Forms of Malaria and Tuberculosis

et al. 2017

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To evaluate the feasibility of developing drugs that may be active against both malaria and tuberculosis (TB) by using in part putative cholesterol transporters in the causative pathogens and through enhancement of passive diffusion in granulomatous TB, artemisinin–cholesterol conjugates were synthesized by connecting the component molecules through various linkers. The compounds were screened in vitro against Plasmodium falciparum (Pf) and Mycobacterium tuberculosis (Mtb). Antimalarial activities (IC50) against Pf drug‐sensitive NF54, and drug‐resistant K1 and W2 strains ranged from 0.03–2.6, 0.03–1.9, and 0.02–1.7 μm. Although the compounds are less active than the precursor artemisinin derivatives, the cholesterol moiety renders the compounds relatively insoluble in the culture medium, and variation in solubilities among the different compounds may reflect in the range of efficacies observed. Activities against Mtb H37Rv were assessed using a standardized colony‐forming unit (CFU) assay after 24 h pretreatment of cultures with each of the compounds. Percentage inhibition ranged from 3–38 % and 18–52 % at 10 and 80 μm, respectively. Thus, in contrast to the comparator drug artemether, the conjugates display enhanced activities. The immediate aims include the preparation of conjugates with enhanced aqueous solubilities, assays against malaria and TB in vivo, and for TB, assays using an infected macrophage model and assessment of granuloma influx.

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Section: Introductionmentioning

confidence: 99%

Preliminary Evaluation of Artemisinin–Cholesterol Conjugates as Potential Drugs for the Treatment of Intractable Forms of Malaria and Tuberculosis

et al. 2017

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“…In previous studies, we have shown that old, potent drug scaffolds can be optimized into clinical candidates (2). Menoctone represents an interesting case in which there was evidence of efficacy against multiple stages, although much was not known since the drug was abandoned shortly after its discovery.…”

Section: Discussionmentioning

confidence: 99%

“…The increased prevalence of drug-resistant parasites and insecticide-resistant vectors continues to drive the need for new treatments for this disease. New drugs are urgently needed, and in some cases old compounds with proven antimalarial activity can serve as the basis for lead optimization of new potent antimalarial drugs (2). Menoctone, also known as 2-hydroxy-3-(8-cyclohexyloctyl)-1,4-naphthoquinone, was first synthesized by Fieser et al in 1948 (3).…”

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Menoctone Resistance in Malaria Parasites Is Conferred by M133I Mutations in Cytochrome b That Are Transmissible through Mosquitoes

Blake

Johnson

Siegel

et al. 2017

Antimicrob Agents Chemother

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Malaria-related mortality has slowly decreased over the past decade; however, eradication of malaria requires the development of new antimalarial chemotherapies that target liver stages of the parasite and combat the emergence of drug resistance. The diminishing arsenal of anti-liver-stage compounds sparked our interest in reviving the old and previously abandoned compound menoctone. In support of these studies, we developed a new convergent synthesis method that was facile, required fewer steps, produced better yields, and utilized less expensive reagents than the previously published method. Menoctone proved to be highly potent against liver stages of Plasmodium berghei (50 percent inhibitory concentration [IC 50 ] ϭ 0.41 nM) and erythrocytic stages of Plasmodium falciparum (113 nM). We selected for resistance to menoctone and found M133I mutations in cytochrome b of both P. falciparum and P. berghei. The same mutation has been observed previously in atovaquone resistance, and we confirmed cross-resistance between menoctone and atovaquone in vitro (for P. falciparum) and in vivo (for P. berghei). Finally, we assessed the transmission potential of menoctone-resistant P. berghei and found that the M133I mutant parasites were readily transmitted from mouse to mosquitoes and back to mice. In each step, the M133I mutation in cytochrome b, inducing menoctone resistance, was confirmed. In summary, this study is the first to show the mechanism of resistance to menoctone and that menoctone and atovaquone resistance is transmissible through mosquitoes.

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Section: Graphical Abstractmentioning

confidence: 99%

“…6 The third partner is logically constructed about the 4(1H)-quinolone scaffold. In addition to being used clinically against a variety of infectious diseases including tuberculosis, 7 certain quinolones have acquired lead status for development of drugs for treatment of toxoplasmosis 8,9 and malaria 10,11,12 respectively.Our attention is drawn to decoquinate (DQ, 1) that has been used for many years in veterinary medicine largely coadministered with poultry feed for treatment of coccidiosis wherein it displays negligible toxicity. 13,14 It is also used against other apicomplexan infections in animals 15 and is highly active in a murine model against Toxoplasma gondii.…”

mentioning

confidence: 99%

Straightforward conversion of decoquinate into inexpensive tractable new derivatives with significant antimalarial activities

Beteck

Coertzen

Smit

et al. 2016

Bioorganic & Medicinal Chemistry Letters

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As part of a programme aimed at identifying rational new triple drug combinations for treatment of malaria, tuberculosis and toxoplasmosis, we have selected quinolones as one component, given that selected examples exhibit exceptionally good activities against the causative pathogens of the foregoing diseases. The quinolone decoquinate (DQ), an old and inexpensive coccidiostat, displays anti-malarial activity in vitro against Plasmodium falciparum (Pf). However, because of its exceedingly poor solubility in water or organic solvents, development of DQ as a drug is problematical. We have therefore converted DQ in straightforward fashion into tractable new derivatives that display good activities in vitro against chloroquine-sensitive NF54 and multidrug-resistant K1 and W2 Pf, and relatively low toxicities against human fibroblast cells. The most active compound, the N-acetyl derivative 30, is 5-fold more active than DQ against NF54 and K1 and equipotent with DQ against W2. It possesses an activity profile against all strains comparable with that of the artemisinin derivative artesunate. Overall, this compound and the other accessible and active derivatives serve as an attractive template for development of new and economic lead quinolones. Graphical Abstract 1Under a programme designed to develop new triple drug combinations for the treatment of malaria, tuberculosis, and toxoplasmosis, 1 we are preparing and evaluating efficacies of compound sets based on combinations of oxidant and redox drugs 2 coupled with a third partner with a different mode of action. In the case of malaria, the need to develop new drug combinations is particularly pressing. 3 Chemotherapy coupled with vector control and inculcation of public awareness has reduced mortality due to malaria by over 66% since 2000. 4 However, the emergence of malaria parasites resistant to the current clinically-used artemisinin derivatives 5 mandates the urgent development of newer artemisinin derivatives. Such derivatives must be incapable of providing the active metabolite dihydroartemisinin (DHA) common to the current clinical artemisinins, and should be rationally combined with the redox drug and a third combination partner to counter resistance and inhibit spread of resistant phenotypes by blocking transmission. 6 The third partner is logically constructed about the 4(1H)-quinolone scaffold. In addition to being used clinically against a variety of infectious diseases including tuberculosis, 7 certain quinolones have acquired lead status for development of drugs for treatment of toxoplasmosis 8,9 and malaria 10,11,12 respectively.Our attention is drawn to decoquinate (DQ, 1) that has been used for many years in veterinary medicine largely coadministered with poultry feed for treatment of coccidiosis wherein it displays negligible toxicity. 13,14 It is also used against other apicomplexan infections in animals 15 and is highly active in a murine model against Toxoplasma gondii. 16 Activity of DQ against malaria including P. berghei 17 in mic...

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

Cited by 21 publications

References 51 publications

Preliminary Evaluation of Artemisinin–Cholesterol Conjugates as Potential Drugs for the Treatment of Intractable Forms of Malaria and Tuberculosis

Preliminary Evaluation of Artemisinin–Cholesterol Conjugates as Potential Drugs for the Treatment of Intractable Forms of Malaria and Tuberculosis

Menoctone Resistance in Malaria Parasites Is Conferred by M133I Mutations in Cytochrome b That Are Transmissible through Mosquitoes

Straightforward conversion of decoquinate into inexpensive tractable new derivatives with significant antimalarial activities

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