4(1H)-quinolones having antimalarial activity with reduced chemical resistance
Inventors
Manetsch, Roman • Cross, Richard Matthew • Namelikonda, Niranjan Kumar • Kyle, Dennis Edward • Mutka, Tina Susanna • LaCrue, Alexis Nichole • Maignan, Jordany Richarlson • Saenz, Fabian Ernesto
Assignees
University of South Florida • University of South Florida St Petersburg
Publication Number
US-8877752-B2
Publication Date
2014-11-04
Expiration Date
2032-10-26
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Abstract
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.
Core Innovation
The disclosure provides novel 4(1H)-quinolone derivatives, particularly phenoxyethoxy-quinolones and 7-(2-phenoxyethoxy)quinolin derivatives, which are effective in inhibiting or eliminating the viability of at least one stage in the life cycle of malarial parasites. These compounds are designed to show a reduced propensity for the development of chemical resistance in the parasite. The compounds may be administered alone, in combination with other disclosed derivatives, or with other antimalarial agents, and formulated for therapeutic or prophylactic use in animals or humans susceptible to Plasmodium infection.
The invention addresses the difficulty in malaria drug development arising from the parasite's multiple life-cycle stages and the rapid emergence of multidrug resistance against existing agents like atovaquone and artemisinin-based therapies. Many current drugs are limited by poor activity across the parasite's life-cycle or the rapid selection of resistant Plasmodium strains. In particular, existing quinolone-based compounds showed efficacy but were quickly undermined by resistance development.
This invention introduces optimized quinolone scaffolds, including several substitutions at the 2-, 3-, 6-, and 7-positions, to achieve strong antimalarial activity against both blood and liver stages of the parasite and to minimize cross-resistance with other compounds such as atovaquone. The presented compounds can be part of pharmaceutical compositions delivered as single or multiple doses for treating or preventing malarial infections, with evidence of selective activity and decreased cytotoxicity to mammalian cells.
Claims Coverage
The patent contains several independent claims, each directed to inventive features regarding the composition, structure, and use of phenoxyethoxy-quinolone derivatives with antimalarial activity and reduced chemical resistance.
Compounds having Formula I or II with specific substitution patterns
The invention covers compounds of Formula I or II, where: - In Formula I: R1 can be H, ethyl, an aryl, carboxymethyl, or a halogen; R2 can be 2-phenoxyethoxy, methoxy, methoxymethoxy, 3-hydroxy-propoxy, 2-ethyl-3-oxo-butyricacid, 2-morpholino-4-yl-ethoxy-, 2-dimethylamino-ethoxy, or 3-(4-phenyl-piperazin-1-yl)-propoxy; R3 can be H, butyrate, a halogen, methyl, or methoxy; and R4 can be H or methyl. - In Formula II: R5 is an H or an alkyl, and Ar is an aromatic group chosen from: phenyl, pyridin-4-yl, pyridin-3-yl, 4-(trifluoromethyl)phenyl, 4-fluorophenoxyphenyl, 4-((4-(trifluoromethoxy)phenoxy)methyl)phenyl), (2-methyl-4-(4-(trifluoromethoxy)phenoxy)phenyl), (2-methyl-4-(trifluoromethyl)phenyl), (2,4-dimethylphenyl), (2-fluoro-4-(trifluoromethyl)phenyl), (4-chloro-2-methylphenyl), and (3,5-dimethylisooxazol-4-yl). The claim embraces specific compounds enumerated in the disclosure, including 6-butyl-2-methyl-7-(2-phenoxyethoxy)quinolin-4(1H)-one, 6-butyl-3-ethyl-2-methyl-7-(2-phenoxyethoxy)quinolin-4(1H)-one, and multiple others with defined substituents.
Pharmaceutically acceptable composition of specific 4(1H)-quinolone derivatives
The invention covers a pharmaceutically acceptable composition comprising a therapeutic amount of at least one of the specified compounds, such as 6-butyl-2-methyl-7-(2-phenoxyethoxy)quinolin-4(1H)-one, 6-butyl-3-ethyl-2-methyl-7-(2-phenoxyethoxy)quinolin-4(1H)-one, and similar derivatives, and optionally a pharmaceutically acceptable carrier. The composition is defined by the inclusion of at least one of the specific quinolone compounds listed in the claims, designed to be effective when administered to a recipient animal or human as a single or multiple dosage in reducing or preventing malarial infection.
Method of reducing the viability of malarial parasites using the disclosed compounds
The invention covers a method wherein a therapeutically effective amount of a pharmaceutically acceptable composition containing any of the listed 4(1H)-quinolone compounds is administered to an animal or human subject to reduce the viability of a population of malarial parasites. The method specifically includes administration for both therapeutic and prophylactic purposes, using compounds such as those specifically named in the claim text (e.g., 6-butyl-2-methyl-7-(2-phenoxyethoxy)quinolin-4(1H)-one and others).
In summary, the inventive features primarily include: (1) novel 4(1H)-quinolone derivatives with defined substitution patterns, (2) pharmaceutical compositions containing such compounds, and (3) methods of using these compounds for treating or preventing malarial infections in animals or humans.
Stated Advantages
The compounds demonstrate effective inhibition or elimination of at least one stage in the life-cycle of the malarial parasite.
These compounds show a reduced propensity to induce chemical resistance in the target parasite as compared to prior art compounds.
The disclosed derivatives exhibit selectivity with minimal cytotoxicity to mammalian cells at relevant concentrations.
Certain compounds provide potent antimalarial activity against multidrug-resistant strains, including atovaquone-resistant Plasmodium falciparum.
Pharmaceutical compositions can offer efficacy as single or multiple dose regimens for both therapy and prophylaxis.
Documented Applications
Administration of the compounds to animal or human subjects to reduce or eliminate malarial parasite infection.
Prophylactic administration to reduce the likelihood of onset or establishment of Plasmodium infection when given prior to exposure.
Therapeutic compositions formulated for single use or for multiple doses over time to decrease parasite viability or prevent infection.
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