Acridone compounds
Inventors
Riscoe, Michael K. • Winter, Rolf W. • Kelly, Jane X. • Hinrichs, David J. • Smilkstein, Martin J.
Assignees
Oregon Health and Science University • US Department of Veterans Affairs • Government of the United States of America
Publication Number
US-9399625-B2
Publication Date
2016-07-26
Expiration Date
2027-11-13
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Abstract
(A1) 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 demonstrate the ability to treat parasitic infections such as malaria and toxoplasmosis, and to sensitize resistant cells, including multidrug resistant cells, to other therapeutic agents. The invention also covers pharmaceutical compositions containing these acridone compounds and methods for their administration.
The invention addresses the problem of multidrug resistant parasitic infections, particularly malaria, which remains a major global health issue. Chloroquine, once the 'gold standard' antimalarial, has become largely ineffective due to the emergence of resistant strains of Plasmodium species. Resistance extends beyond chloroquine to quinoline, antifolate-based drugs, and even artemisinin derivatives, severely limiting treatment options, especially in impoverished and tropical areas.
Moreover, multidrug resistance is a broader problem affecting diseases such as tuberculosis, amoebic dysentery, sleeping sickness, leishmaniasis, and AIDS pneumonia, where resistance renders formerly effective drugs ineffective. There is thus a critical need for new antimalarial drugs as well as agents capable of reversing multidrug resistance. Additionally, parasitic infections have been associated with psychotic diseases like schizophrenia, creating a further need for anti-psychotic drugs. The disclosed acridone compounds provide solutions by acting as antiparasitic agents and chemosensitizers to reverse multidrug resistance, and potentially also for treating psychotic diseases.
Claims Coverage
The patent includes two independent compound claims and two independent method/composition claims covering the use and administration of acridone compounds and their derivatives. These claims collectively cover the novel chemical structures, pharmaceutical compositions containing these compounds, and the therapeutic methods employing them.
Novel acridone compounds with specific structural features
The invention claims compounds defined by a specific acridone formula characterized by variable substituents including R, X, n, Y, R5, R1, G, and others. The compounds include both aromatic and heterocyclic ring systems such as pyrrolidino, pyridine, piperidino, morpholino, piperazino, imidazolyl, pyrazolyl or triazolyl.
Pharmaceutical compositions containing acridone compounds
Pharmaceutical formulations comprising an effective amount of the acridone compounds and a pharmaceutically acceptable carrier are claimed. These compositions may further include a second compound such as anticancer, antimalarial, antiparasitic, antibiotic, or antiretroviral agents. The compositions encompass synergistic combinations, particularly with antimalarial quinolines and Cinchona alkaloids like quinine or quinidine.
Methods for treating parasitic infections by administering acridone compounds
Methods for inhibiting or treating parasitic infections in subjects by administering therapeutically effective amounts of disclosed acridone compounds are claimed. These methods cover prophylactic administration, treatment of malaria including infections by various Plasmodium species, treatment of toxoplasmosis, and achieving curative doses over specific timeframes.
Methods for potentiating drugs to treat multidrug resistant disorders
Methods for potentiating primary drugs against multidrug resistant parasitic infections by administering effective amounts of the acridone compounds are claimed. This includes treatment of infections caused by Entamoeba histolytica, trypanosomiasis, leishmaniasis, toxoplasmosis, and malaria, thereby enhancing drug efficacy against resistant pathogens.
The independent claims collectively cover novel acridone compounds with defined chemical structures, their use in pharmaceutical compositions with or without additional therapeutic agents, and methods for treating parasitic infections and potentiating drugs in multidrug resistant disorders.
Stated Advantages
The acridone compounds effectively reverse multidrug resistance, restoring or enhancing the efficacy of existing therapeutic agents against resistant parasitic and neoplastic cells.
They exhibit potent antiparasitic activity, including against multidrug resistant Plasmodium species causing malaria, with favorable oral bioavailability and low toxicity at therapeutic doses.
They form soluble complexes with heme, inhibiting heme aggregation and thereby interfering with parasite survival mechanisms, representing a novel mode of action.
Combinations of acridone compounds with other antimalarial agents, such as quinine, show synergistic effects, allowing dose reductions and improved therapeutic outcomes.
Documented Applications
Treatment of parasitic infections caused by organisms including Plasmodium species (malaria), Toxoplasma gondii (toxoplasmosis), Mycobacterium tuberculosis, and Pneumocystis carinii.
Use as chemosensitizers to reverse multidrug resistance in parasitic infections, cancer, bacterial, viral, protozoal, and fungal diseases.
Combination therapy with other drugs to potentiate efficacy against multidrug resistant pathogens, including use with antimalarial agents such as quinolines, artemisinins, antifolates, and Cinchona alkaloids.
Prophylactic administration to prevent malaria infection in subjects exposed to Plasmodium species.
Treatment of psychotic diseases such as schizophrenia associated with parasitic infections.
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