- 4(1H)-Quinolones Having Antimalarial Activity With Reduced Chemical Resistance
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Provided are 4(1H)-quinolone derivatives effective in inhibiting or eliminating the viability of at least one of the stages in the life-cycle of the malarial parasite, and to show a reduced propensity to induce resistance to the compound by the target parasite. In particular, the compounds can be derivatives of phenoxyethoxy-quinolones, and including, but not only, 7-(2-phenoxyethoxy)quinolin derivatives. These compounds may be administered by themselves, with at least one other derivative compound, or with other antimalarial compounds, to an animal or human subject. The therapeutic compositions can be and formulated to reduce the extent of a Plasmodium infection in the recipient subject, or to reduce the likelihood of the onset or establishment of a Plasmodium infection if administered prior to the parasite contacting the subject. The therapeutic compositions can be formulated to provide an effective single dose amount of an antimalarial compound or multiple doses for administering over a period of time.
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Paragraph 0171
(2013/05/22)
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- Synthesis, antimalarial activity, and structure-activity relationship of 7-(2-Phenoxyethoxy)-4(1H)-quinolones
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ICI 56,780 (5) displayed causal prophylactic and blood schizonticidal activity (ED50 = 0.05 mg/kg) in rodent malaria models but produced rapid acquisition of parasitological resistance in P. berghei infected mice. Herein we describe the synthesis of analogues of 5 with EC50 as low as 0.15 nM against multidrug resistant P. falciparum. Optimal activity with low cross-resistance indexes (RI) to atovaquone was achieved by introducing ortho-substituted aryl moieties at the 3-position of the 7-(2-phenoxyethoxy)- 4(1H)-quinolone core. (Figure presented
- Cross, R. Matthew,Namelikonda, Niranjan K.,Mutka, Tina S.,Luong, Lisa,Kyle, Dennis E.,Manetsch, Roman
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supporting information; experimental part
p. 8321 - 8327
(2012/02/04)
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- Hydrolysis of N-(Pivaloyloxy)-p-acetotoluidide: N-O Bond Cleavage Reactions of a Model Proximate Carcinogen
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The hydrolysis reactions of N-(pivaloyloxy)-p-acetotoluidide (1a), a model for the carcinogenic metabolites of polycyclic aromatic amides, were investigated by a combination of UV spectroscopy, product analyses, and HPLC methods at 70 deg C over the pH range 2.0-8.0.Under these conditions 1a undergoes exclusive N-O bond cleavage to yield products characteristic of processes involving nitrenium ion pairs.In many ways the reactions of 1a in aqueous solution parallel those of the analogous sulfuric acid ester, 1b.However, two unique products, 3-(pivaloyloxy)-4-methylacetanilide (2b) and 4-acetotoluidide (9), which have no analogues in the reactions of 1b under these conditions, were isolated.The first-order rate constant for the decomposition of 1a, which is independent of pH and buffer composition, is (380 +/- 60)-fold less than the corresponding rate constant for 1b under the same conditions.The characteristics of the hydrolysis reaction of 1a are considerably different from those of the N-acetoxy-N-arylacetamides which undergo a considerable amount of acyl transfer under similar conditions.These results indicate that pivalic acid esters may be more appropriate models for the proximate carcinogens derived from N-hydroxy-N-arylacetamides than are the acetic acid estrs if, indeed, nitrenium ions are the ultimate carcinogens.
- Novak, Michael,Roy, Ajit K.
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p. 4884 - 4888
(2007/10/02)
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- Hydrolysis of N-(Sulfonatooxy)-p-acetotoluidide: Solution Chemistry of Models for Carcinogenic Metabolites of Aromatic Amides
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The hydrolysis reactions of the title compound, a model for the carcinogenic metabolites of polycyclic aromatic amides, were investigated over the pH range 1.0-8.0 by UV spectroscopic methods, product analyses, HPLC, and 1H NMR.This compound is unique among the N-(sulfonatooxy)acetanilides that have been studied to date in that over most of the pH range examined it exhibits non-first-order reaction kinetics.Product analyses indicate that, like the other N-(sulfonatooxy)acetanilides, the hydrolysis of this compound involves N-O bond cleavage, and the kinetics of the N-O bond cleavage process are consistent with a mechanism that includes generation of nitrenium ion-sulfate ion pairs.Four transient species, 9-12, were generated in sufficient quantity to be detected during the hydrolysis reaction.On the basis of isolated decomposition products and kinetic and spectral data obtained during the course of the hydrolysis reaction, the intermediate 9 was identified as 4-hydroxy-4-methylcyclohexa-2,5-dien-1-one N-acetylimine, while 10 and 11 were identified as the isomeric cis- and trans-N-acetyl-2-amino-5,6-dihydroxy-5-methylcyclohexa-1,3-dienes.These species are analogous to materials isolated by Gassman and Granrud from the methanolysis reactions of the methanesulfonate ester of N-hydroxy-p-acetotoluidide.The fourth intermediate, 12, has been tentatively identified as 4-(sulfonatooxy)-4-methylcyclohexa-2,5-dien-1-one.The pH dependence of the hydrolysis reactions of 9 and 10 have also been thoroughly investigated.Both are subject to acid catalysis of hydrolysis and give rise to a number of products.
- Novak, Michael,Roy, Ajit K.
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p. 571 - 580
(2007/10/02)
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