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-11753408-B2
Publication Date
2023-09-12
Expiration Date
2037-10-13
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Abstract
Disclosed are compounds of formula (I) and formula (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
This invention provides compounds of formula (I) and formula (II) that are capable of blocking the transmission of Plasmodium parasites. The compounds feature various substitutions on aryl and heteroaryl groups and include pharmaceutically acceptable salts. Additionally, methods of treating or preventing malaria involve administering therapeutically effective amounts of these compounds alone or in combination with other antimalarial agents such as elesclomol or NVP-AUY922.
The problem addressed by this invention is the limitation of current antimalarial therapies which primarily target asexual parasites causing symptoms but do not effectively block malaria transmission. Sexual stage gametocytes, especially mature ones, have a lifespan exceeding three weeks and are not effectively cleared by existing treatments except primaquine, which has safety concerns due to hemolytic anemia risks in certain patients. Consequently, asymptomatic carriers remain infectious, complicating malaria eradication efforts. There is an urgent need for antimalarial agents with potent activities against both sexual and asexual parasites to improve therapeutic outcomes and contribute to global malaria eradication.
Claims Coverage
The patent presents two independent claims covering compounds of formula (I) and formula (II) with specific chemical features and methods of use to block Plasmodium transmission.
Compounds of formula (I)
Compounds characterized by having A as CR5 or N, B as CR3═CR4 or NR6, with R1 being C6-10 aryl or heteroaryl substituted with groups including —CN, cyanomethyl, —SO2R13, —SO2NHR15, or —CONR11R12, and various detailed substituents for R2, R3, R4, R5, and others, including pharmaceutically acceptable salts.
Compounds of formula (II)
Compounds characterized by A as CR5 or N, B as CR3═CR4 or NR6, where R1 is C6-10 aryl or heteroaryl substituted with C1-12 alkyl, C3-10 cycloalkyl, alkoxy, —CF3, heterocyclyl, —CONR11R12, —SO2NHR16, or CN, and R2 selected from a specified list of heteroaryl and aryl groups, including pharmaceutically acceptable salts.
Methods of blocking Plasmodium transmission and treatment of malaria
Methods comprising administering therapeutically effective amounts of compounds of formula (I) or (II) to mammals in need, optionally combined with selected antimalarial compounds such as elesclomol, NSC174938, NVP-AUY922, and others as listed, to block transmission or treat malaria by killing or arresting gametocyte stage Plasmodium organisms.
The claims cover novel heteroaryl and aryl substituted compounds capable of blocking malaria transmission and treating malaria infections, particularly targeting gametocytes, along with methods of synthesis and pharmaceutical compositions comprising these compounds.
Stated Advantages
The compounds and methods of the invention kill all stages of malaria parasites.
Documented Applications
Blocking transmission of Plasmodium parasites by administering compounds to mammals.
Treating or preventing malaria by killing or arresting the growth of Plasmodium gametocytes.
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