Diphenyl substituted thiophene-2-amide derivatives and pharmaceutical compositions thereof useful as antimicrobial
Inventors
Wu, Fan • Lu, Erhu • Sun, Shengguo • Barden, Christopher J.
Assignees
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Publication Number
US-11306067-B2
Publication Date
2022-04-19
Expiration Date
Abstract
Compounds or pharmaceutical acceptable salts thereof of Formula (I), in which RM have the meaning described herein and pharmaceutical compositions thereof useful as antimicrobial and/or adjuvant:
Core Innovation
Diphenyl-substituted thiophene-2-amide derivatives of Formula I, including pharmaceutically acceptable salts, are described as antimicrobial and/or antimicrobial adjuvant compounds. The derivatives are defined by substituent constraints in Formula I, including R1 and R2 as fluoro or chloro; R3 and R4 as alkyl; R5 as hydrogen or alkyl; and R6 as an amide, a sulfonamide, or a —C(CF3)2OH group.
The described compounds are associated with inhibition of acyl carrier protein (ACP) synthase (AcpS), including inhibition involving apo-ACP and holo-ACP, and the resulting effects on bacterial lipid metabolism. The patent describes a rationale in which AcpS inhibition is linked to changes such as potential membrane porosity and efflux pump dysfunction, which supports improved antibiotic entry and an antimicrobial adjuvant effect.
Therapeutic methods are described in which antimicrobial treatment is achieved by administering the antimicrobial compound alone or in combination, including combination therapy that pairs an antimicrobial adjuvant compound with a partner antibiotic. Microbial infections addressed include Gram-positive bacteria and Gram-negative pathogens, with examples explicitly including MRSA and VRE, as well as bacterial species such as Staphylococcus aureus, Enterococcus sp., Pseudomonas aeruginosa, Acinetobacter baumannii, Escherichia coli, and Klebsiella pneumoniae.
Claims Coverage
The independent claim covers a compound (or pharmaceutically acceptable salt) defined by Formula I, and dependent claims primarily refine the substituent selection and narrow the treatment to specific microbial causes and combination partners. In the provided set, one independent claim is explicitly identified and its core structural coverage is the Formula I definition with restricted substituents.
Formula I diphenyl-substituted thiophene-2-amide compound
A compound, or a pharmaceutically acceptable salt thereof, of Formula I in which R1 and R2 are each independently fluoro or chloro; R3 and R4 are each independently alkyl; R5 is hydrogen or alkyl; and R6 is amide, sulfonamide or —C(CF3)2OH.
Overall, the claim coverage in the provided material centers on Formula I diphenyl-substituted thiophene-2-amide compounds defined by specific substituent limitations, with dependent claims further narrowing specific substituent embodiments and treatment contexts involving microbial infection categories and named combination antimicrobial partners.
Stated Advantages
Antimicrobial activity and/or antimicrobial adjuvant effect.
Improved antibiotic entry supported by the described link between AcpS inhibition and membrane porosity/efflux pump dysfunction.
Documented Applications
Treating microbial infections by administering the antimicrobial compound alone or in combination therapy.
Treatment of infections substantially caused by Gram-positive bacteria.
Treatment of microbial infections substantially caused by Pseudomonas aeruginosa, Klebsiella pneumoniae, Acinetobacter baumannii, or E. coli.
Use in combination therapy involving named additional antimicrobials including colistin, ampicillin, erythromycin, or azithromycin.
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