Compounds and method for blocking transmission of malarial parasite
Inventors
HUANG, Wenwei • Li, Hao • Sun, Wei • Huang, Xiuli • Patel, Paresma R. • Sun, Hangmao • Zheng, Wei • Lu, Xiao • Sanderson, Philip E. • KIM, Myunghoon • Orr, Meghan J. • TAWA, Gregory J. • Williamson, Kim C.
Assignees
Loyola University Chicago • US Department of Health and Human Services
Publication Number
US-10988472-B2
Publication Date
2021-04-27
Expiration Date
2037-10-13
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Abstract
Disclosed are compounds of formula (I) and formula (II): (I) (II) wherein R1, R2, A, and B are as defined herein. Also disclosed is a method of blocking transmission of a Plasmodium parasite and a method of treating or preventing malaria comprising administering to an animal an effective amount of a first compound of formula (I) or (II) either alone or in combination with a second compound selected from elesclomol, NSC174938, NVP-AUY922, Maduramicin, Narasin, Alvespimycin, Omacetaxine, Thiram, Zinc pyrithione, Phanquinone, Bortezomib, Salinomycin sodium, Monensin sodium, Dipyrithione, Dicyclopentamethylene-thiuram disulfide, YM155, Withaferin A, Adriamycin, Romidepsin, AZD-1152-HQPA, CAY10581, Plicamycin, CUDC-101, Auranofin, Trametinib, GSK-458, Afatinib, and Panobinostat.
Core Innovation
The invention provides compounds of formula (I) and formula (II) characterized by specific chemical structures with defined substitutions such as aryl, heteroaryl, carbamate, and sulfonyl groups. These compounds are designed to block transmission of Plasmodium parasites, particularly targeting sexual stage gametocytes. The invention includes pharmaceutical compositions containing these compounds and methods for treating or preventing malaria by administering these compounds alone or in combination with other antimalarial agents.
The problem addressed stems from the insufficient effectiveness of current antimalarial therapies against the sexual stage of Plasmodium parasites (gametocytes), which are responsible for transmission to mosquitoes and consequent spread of malaria. Existing drugs effectively clear asexual parasites causing symptoms but fail to clear mature gametocytes that survive for weeks, maintaining infectivity despite treatment. Primaquine is effective against gametocytes but is limited by safety issues in certain populations. Hence, there is an urgent need for new antimalarial agents active against both sexual and asexual parasite stages to achieve better therapeutic outcomes and disease eradication.
Claims Coverage
The patent discloses two independent claims covering compounds of formula (I) and formula (II), pharmaceutical compositions comprising these compounds, and methods of blocking Plasmodium transmission or treating malaria using these compounds optionally combined with other antimalarials. The inventive features relate to the compounds' structural characteristics, their combinations, and therapeutic uses.
Compounds of formula (I) with defined substituents
Compounds defined by formula (I) where A is CR5 or N, B is CR3═CR4 or NR6; R1 is C6-10 aryl or heteroaryl substituted by groups such as —CN, cyanomethyl, —SO2R13, —SO2NHR15, and —CONR11R12 optionally further substituted; R2 encompasses a broad list of heteroaryl and aryl groups; R3-R16 are variously hydrogen, alkyl, aryl or heterocyclyl groups or their combinations; including provisos limiting certain substitutions.
Compounds of formula (II) with defined substituents
Compounds defined by formula (II) where A is CR5 or N; R1 is C6-10 aryl or heteroaryl with substituents from C1-12 alkyl, cycloalkyl, alkoxy, —CF3, heterocyclyl, —CONR11R12, —SO2NHR16, and CN; R2 includes selected heteroaryl and aryl groups; R11, R12, R14, and R16 have defined substituents or ring systems; pharmaceutically acceptable salts also covered.
Pharmaceutical compositions
Compositions comprising a compound or a pharmaceutically acceptable salt of formula (I) or (II) combined with a pharmaceutically acceptable carrier suitable for various administration routes.
Methods of blocking Plasmodium transmission and treating malaria
Methods involving administering therapeutically effective amounts of a compound of formula (I) or (II) alone or in combination with selected antimalarial compounds including listed drugs such as elesclomol, NSC174938, NVP-AUY922, and others to mammals in need, targeting Plasmodium parasites in the gametocyte stage.
The claims cover structurally defined compounds (formulas I and II), their pharmaceutical compositions, and their therapeutic use for blocking Plasmodium transmission and treating malaria, optionally in combination with other antimalarial agents.
Stated Advantages
The compounds kill all stages of malaria parasites.
Documented Applications
Blocking transmission of Plasmodium parasites in mammals in need of such treatment.
Treating or preventing malaria by killing or arresting the growth of Plasmodium organisms in a mammal, especially parasites in the gametocyte stage.
Use in combination therapies with other antimalarial compounds such as elesclomol, NSC174938, NVP-AUY922, maduramicin, narasin, and others.
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