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-9974796-B2
Publication Date
2018-05-22
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) and their use in treating or preventing malaria in animals, including humans, by administering an effective amount of such inhibitors or their combinations. The compounds of the invention are represented by formulas I, IV, and V, and these compounds or combinations thereof exhibit synergistic killing of parasites. PSAC is a membrane channel on infected red blood cells that mediates the uptake of critical nutrients necessary for parasite survival.
Malaria is a significant infectious disease caused by Plasmodium parasites, with symptoms ranging from fever to severe anemia and kidney failure, leading to high morbidity and mortality, especially among young children in Africa. Treatment relies on antimalarial drugs, but resistance has developed against all current drugs, and no effective vaccine exists. Hence, there is a strong need to discover and develop new antimalarials.
PSAC increases red blood cell permeability to a broad range of solutes vital for parasite growth and has unique features, including high exclusion of Na+ to prevent osmotic lysis of infected cells. The channel's surface location on erythrocytes allows direct antagonist access and prevents resistance via drug extrusion mechanisms seen with drugs targeting parasite intracellular compartments. The invention aims to exploit PSAC as a target for antimalarial compounds, providing novel inhibitors that block nutrient acquisition by the parasite and effectively kill it, especially when used in combinations that act synergistically.
Claims Coverage
The patent includes one independent claim focusing on a method of providing prophylaxis or treatment against malaria by administering a compound of formula V to an animal.
Method of prophylaxis or treatment against malaria using a compound of formula V
Administering an effective amount of a compound of formula V or its pharmaceutically acceptable salt to an animal, preferably a human, to prevent or treat malaria.
Specific substitutions in compound of formula V
The compound of formula V wherein substituents R13 are methyl or methoxy; R11 is alkyl; R12 is alkyl, cycloalkyl, or aryl optionally substituted with groups such as alkyl, alkoxy, halo, hydroxy, nitro, cyano, amino, alkylamino, aminoalkyl, alkylcarbonyl, alkoxycarbonyl, aminocarbonyl, and formyl; and variants thereof where R11 is hydrogen and R12 is cycloalkyl or aryl optionally substituted with alkyl and/or alkoxy.
Combination administration
Methods involving administration of the compounds alone or in combination with other compounds (including those outside formulas I, IV, and V) to enhance prophylaxis or treatment, including specific examples of compound pairs and further compounds for administration.
The claims cover a method of prophylaxis or treatment for malaria by administering compounds of formula V with specified substituents, alone or in combination with other compounds, emphasizing their use for effective antimalarial therapy in animals such as humans.
Stated Advantages
Enhanced parasite killing through synergistic effects when combinations of two or more compounds targeting distinct PSAC channel components are administered.
PSAC's exposed location on infected red blood cells enables direct access to antagonists and prevents resistance mechanisms associated with intracellular drug targets.
High selectivity and unique functional properties of PSAC provide a novel and constrained target essential for parasite nutrient uptake and survival.
Documented Applications
Use of PSAC inhibitors in pharmaceutical compositions for preventing or treating malaria in animals including humans.
Administration of combinations of compounds of formulas I, IV, and V to achieve synergistic killing of malarial parasites.
Methods for preparing medicaments for preventing malaria or treating animals afflicted with malaria by administering compounds of formulas I, IV, and V or their pharmaceutically acceptable salts.
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