Treatment of Acanthamoeba or Balamuthia trophozoites and/or cysts
Inventors
Boykin, David W. • Kyle, Dennis E. • Rice, Christopher A. • Farahat, Abdelbasset A.
Assignees
University of Georgia Research Foundation Inc • Georgia State University Research Foundation Inc • University of South Florida St Petersburg
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Publication Number
US-12433872-B2
Publication Date
2025-10-07
Expiration Date
Abstract
Compounds, compositions, and methods for the treatment of infections caused by Acanthamoeba or Balamuthia mandrillaris trophozoites and/or cysts and for the disinfection of solids and/or liquids, such as medical and personal care items, for example contact lenses, that may harbor Acanthamoeba trophozoites and/or cysts are provided.
Core Innovation
The invention provides compounds of Formula 2 or Formula 3, or pharmaceutically acceptable salts thereof, including benzo[d]imidazole-based carboximidamide, benzimidazole-based amidine/carboximidamide, and diamidine-containing compounds. The compounds are defined by specific substituent-selection constraints for R3 and R4, R5, R6 and R7, R8, R9 and R10, together with RX and RY, o and p, and RA and RB. At least one of each paired set R3/R4, R6/R7, and R9/R10 is not hydrogen, and the substituent categories include halo, C1-C4 alkoxy, C1-C4 haloalkyl, and C1-C6 alkyl.
The disclosure includes representative structures and example compounds within the Formula 2 and Formula 3 frameworks, including substituted phenyl motifs, fused heteroaromatic/aminated ring systems, and benzimidazole-6-carboximidamide tetrahydrochloride derivatives. The embodiments include fluorine, halogen, cyano, methoxy, and related derivatives exemplified by compound K, L, and M/N variants, as well as additional named structures and salts. The compounds are presented in the context of biological activity against Acanthamoeba and Balamuthia mandrillaris, including free-living and cystic forms.
The embodiments further describe treating Acanthamoeba infections by administering a compound described in the patent together with an additional therapeutic agent. The additional therapeutic agent includes gramicidin, voriconazole, miconazole nitrate, pentamidine, octamidine, fluconazole, and miltefosine, and the treatment scope includes Acanthamoeba keratitis, granulomatous amoebic encephalitis (GAE), CNS infection, cutaneous infection, and eye infection. The disclosure also includes disinfection of Acanthamoeba from solid, liquid, or gel objects, including contact lens care solutions and contact lens solutions.
Claims Coverage
The consolidated claim coverage includes three independent claim themes: formula-defined compound claims, a selected compound group claim, and treatment methods for infections caused by Balamuthia mandrillaris or Acanthamoeba. Across the provided excerpts, the inventive features center on Formula 2 or Formula 3 compound definitions with specific substituent constraints, a group-selected compound embodiment, and administration of an effective amount of the disclosed compounds for host treatment or disinfection.
Formula 2 or Formula 3 compounds with constrained substituents
A compound of Formula 2 or Formula 3, or a pharmaceutically acceptable salt thereof, wherein R3 and R4 are independently selected from hydrogen, halo, C1-C4 alkoxy, and C1-C4 haloalkyl with at least one of R3 and R4 not hydrogen; R5 is selected from halo, C1-C4 alkoxy, and C1-C4 haloalkyl; R6 and R7 are independently selected from hydrogen, halo, C1-C4 alkoxy, and C1-C4 haloalkyl with at least one of R6 and R7 not hydrogen; R8 is selected from halo, C1-C4 alkoxy, and C1-C4 haloalkyl; R9 and R10 are independently selected from hydrogen, halo, C1-C4 alkoxy, and C1-C4 haloalkyl with at least one of R9 and R10 not hydrogen; RX and RY are independently selected at each occurrence from halo, C1-C4 alkoxy, and C1-C4 haloalkyl; o and p are independently selected from 0, 1, 2, and 3; and RA and RB are independently C1-C6 alkyl.
Compound selected from a specified group
A compound selected from the group consisting of a specified group, or a pharmaceutically acceptable salt thereof, as recited in the partial claim text provided.
Treating infections caused by Balamuthia mandrillaris or Acanthamoeba species
A method for treating an infection caused by Balamuthia mandrillaris or an Acanthamoeba species in a host comprising administering an effective amount of a compound from a specified group, or a pharmaceutically acceptable salt thereof.
Disinfection of Acanthamoeba from objects
A method to disinfect one or more Acanthamoeba species from a solid, liquid, or gel object by administering an effective amount of a disclosed compound, optionally in a pharmaceutically acceptable carrier.
Overall, the claims are directed to formula-defined benzimidazole amidine/carboximidamide or diamidine compounds with strict substituent limits, a claim to a selected compound group, and methods for treating host infections caused by Balamuthia mandrillaris or Acanthamoeba species and for disinfecting Acanthamoeba from objects using the disclosed compounds.
Stated Advantages
Treating and/or preventing Acanthamoeba infections, including Acanthamoeba keratitis.
Treating and/or preventing Balamuthia mandrillaris infections, including granulomatous amoebic encephalitis (GAE).
Reducing and/or eliminating Acanthamoeba on objects, including contact lens care solutions.
Addresses poor cysticidal activity of existing therapies.
Achieves no observed excystation for extended periods in the stated cyst assay context.
Documented Applications
Therapeutic use for treating and/or preventing Acanthamoeba infections, including Acanthamoeba keratitis.
Therapeutic use for treating and/or preventing infections in the central nervous system/skin caused by Acanthamoeba species.
Therapeutic use for treating and/or preventing Balamuthia mandrillaris infections, including granulomatous amoebic encephalitis (GAE).
Disinfecting solutions concept for reducing and/or eliminating Acanthamoeba on objects, including contact lens care solutions.
Disinfection of Acanthamoeba from solid, liquid, or gel objects, including contact lenses, contact lens solutions, and rewetting eye drops, and use with an optical implant [procedural detail omitted for safety].
Treatment of Acanthamoeba keratitis, including Acanthamoeba cysts and trophozoites [procedural detail omitted for safety].
Treatment of infections caused by Balamuthia mandrillaris and granulomatous amoebic encephalitis (GAE) [procedural detail omitted for safety].
Anti-Acanthamoeba activity, including encystation/excystation viability measurements and cysticidal metrics such as cysticidal IC50 and minimum cysticidal concentration (MCC), with reported selectivity index versus A549.
Co-administration with an additional therapeutic agent for treating Acanthamoeba infection and related infections.
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