Inhibitors of the plasmodial surface anion channel as antimalarials
Inventors
Desai, Sanjay A. • Pillai, Ajay D.
Assignees
US Department of Health and Human Services
Publication Number
US-9394316-B2
Publication Date
2016-07-19
Expiration Date
2029-07-15
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Abstract
Disclosed are inhibitors of the plasmodial surface anion channel (PSAC) inhibitors and the use thereof in treating or preventing malaria in an animal such as a human, comprising administering an effective amount of an inhibitor or a combination of inhibitors. An example of such an inhibitor is a compound of formula I, or a pharmaceutically acceptable salt thereof, wherein R1 to R7 are as described herein.
Core Innovation
The invention provides inhibitors of the plasmodial surface anion channel (PSAC) for use in treating or preventing malaria in animals, including humans, by administering an effective amount of one or more such inhibitors. The compounds are represented by formulae I, IV, and V, including various substituents as defined, and may be administered alone or in combination. The invention also provides pharmaceutical compositions containing these compounds and their use as medicaments.
PSAC plays a central role in parasite nutrient acquisition by increasing permeability of infected red blood cells for various nutrients essential to parasite survival. Its unique properties include atypical gating and a very high exclusion of sodium ions, critical to preventing osmotic lysis of infected cells. Unlike parasite targets inside red blood cells, PSAC is located on the erythrocyte surface, allowing direct access by drugs and reducing resistance caused by drug extrusion.
The problem solved by the invention arises from malaria being a major infectious disease without an effective vaccine and increasing drug resistance against all available antimalarials. Thus, there is a need for new antimalarials targeting mechanisms essential for parasite survival. The invention addresses this by providing PSAC inhibitors that effectively block parasite growth, including combinations that demonstrate synergistic killing of parasites, exceeding the efficacy of individual agents alone.
Claims Coverage
The patent includes several independent claims covering methods of preventing or treating malaria by administering compounds of specific chemical formulas.
Method of prophylaxis or treatment using PSAC inhibitors
Administering to an animal an effective amount of a compound selected from groups of chemical structures defined by formulas I, IV, and V, or their pharmaceutically acceptable salts, to prevent or treat malaria.
The independent claims focus on methods of malaria prophylaxis or treatment by administering specific chemical compounds that inhibit the plasmodial surface anion channel, encompassing compounds of formulae I, IV, and V and their salts.
Stated Advantages
The compounds exhibit synergistic killing of malaria parasites when used in combination, leading to greater efficacy than individual compounds alone.
PSAC's exposed location on infected erythrocytes allows direct access by antagonists, minimizing resistance due to drug extrusion.
The inhibitors effectively arrest parasite growth at low micromolar concentrations.
Documented Applications
Preventing malaria in animals, including humans, by administering PSAC inhibitors.
Treating animals afflicted with malaria through administration of effective amounts of compounds of formulas I, IV, and V, alone or in combinations.
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