Acridone compounds
Inventors
Riscoe, Michael K. • Winter, Rolf • Kelly, Jane X. • Hinrichs, David J. • Smilkstein, Martin J.
Assignees
Oregon Health and Science University • US Department of Veterans Affairs
Publication Number
US-8592447-B2
Publication Date
2013-11-26
Expiration Date
2027-11-13
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Abstract
A class of acridone compounds has been discovered that exhibits chemosensitizing and antiparasitic activity. Described herein are pharmaceutical compositions and methods for their use to treat parasitic infections, such as malaria and toxoplasmosis, and to sensitize resistant cells, such as multidrug resistant cells to other therapeutic agents. The pharmaceutical compositions and methods may also be used to treat and/or prevent psychotic diseases such as schizophrenia.
Core Innovation
A class of acridone compounds has been discovered that exhibits chemosensitizing and antiparasitic activity. These compounds are represented by chemical formulas that include various substitutions on the acridone ring system, such as alkyl, halo, haloalkyl, amino, and other functional groups, and include pharmaceutically acceptable salts, prodrugs, regioisomers, enantiomers, diastereoisomers, and geometric isomers. The compounds can be used alone or in combination with other therapeutic agents, particularly for treating parasitic infections, multidrug resistant cells, and psychotic diseases such as schizophrenia.
The invention addresses the problem of multidrug resistance in parasitic diseases, such as malaria caused by Plasmodium species, where conventional antimalarial drugs like chloroquine have become ineffective due to development of resistant strains. Multidrug resistance also impacts treatment of other infectious diseases and cancer, rendering previously effective drugs ineffective. Furthermore, parasitic infections have been linked to psychotic diseases, underscoring the need for new antiparasitic and antipsychotic agents. Thus, there is a significant need for new compounds capable of overcoming drug resistance and effectively treating parasitic infections and related diseases.
Claims Coverage
The patent includes multiple independent claims covering acridone compounds, pharmaceutical compositions comprising these compounds, and methods of inhibiting growth of Plasmodium species. The inventive features encompass the chemical structure of the compounds, their pharmaceutical formulations, combinations with other agents, and therapeutic methods.
Chemical structure of acridone compounds
Claims define a class of acridone compounds characterized by specific substitutions on the acridone ring, including positions and types of substituents such as alkyl chains, halogen or haloalkyl groups, various nitrogen-containing groups, and bridged structures. Specific formulas and embodiments for these compounds are provided, including preferred substituents and substitution patterns.
Pharmaceutical compositions comprising acridone compounds
Claims cover pharmaceutical compositions containing an effective amount of the acridone compounds and pharmaceutically acceptable carriers. These compositions may also include a second compound, such as anticancer, antimalarial, antiparasitic, antibiotic, or antiretroviral agents. Specific combinations include compositions with antimalarial quinolines and Cinchona alkaloids, including quinine and quinidine.
Methods of inhibiting growth of Plasmodium species
Claims encompass methods for inhibiting growth of Plasmodium parasites by contacting the parasites with a growth inhibitory amount of the acridone compounds. Particular claims specify inhibition of Plasmodium falciparum, Plasmodium vivax, Plasmodium ovale, Plasmodium malariae, or combinations thereof.
The claims collectively cover novel acridone compounds with defined chemical structures, their pharmaceutical formulations including combination therapies, and methods of treating Plasmodium infections by growth inhibition. The invention thus broadly protects the compounds, their use in compositions, and their application in antiparasitic therapy.
Stated Advantages
The acridone compounds effectively reverse multidrug resistance in parasites, restoring the efficacy of drugs to which resistance has developed.
They exhibit potent antimalarial activity against both sensitive and multidrug resistant strains of Plasmodium falciparum, with favorable cytotoxicity and therapeutic indices.
The compounds demonstrate oral bioavailability and in vivo efficacy, including parasitemia suppression and curative effects in mouse models.
They have chemosensitizing properties that synergize with other antimalarial agents, allowing dose reductions and improved treatment outcomes.
The acridones inhibit heme aggregation, a mechanism linked to antiparasitic effect.
The compounds exhibit metabolic stability with active metabolites, potentially extending pharmacodynamic activity.
Documented Applications
Treatment of parasitic infections, especially malaria caused by Plasmodium species, including multidrug resistant strains.
Use as chemosensitizers to sensitize resistant cells, including multidrug resistant parasites and cancers, to other therapeutic agents.
Treatment and prevention of psychotic diseases such as schizophrenia potentially linked to parasitic infections.
Combination therapy with other antimalarial agents such as quinolines, including quinine and chloroquine, and other therapeutic agents.
Prophylactic administration to prevent malaria infection.
Treatment of other parasitic diseases such as toxoplasmosis, trypanosomiasis, leishmaniasis, and infections caused by Mycobacterium and Pneumocystis species.
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