The design, synthesis, and inhibition of Clostridioides difficile spore germination by acyclic and bicyclic tertiary amide analogs of cholate.

Autor: Sharma SK; Department of Pharmaceutical Sciences, Eugene Applebaum College of Pharmacy and Health Sciences, Wayne State University, 259 Mack Avenue, Detroit, MI, 48201, USA., Schilke AR; Department of Pharmaceutical Sciences, Eugene Applebaum College of Pharmacy and Health Sciences, Wayne State University, 259 Mack Avenue, Detroit, MI, 48201, USA., Phan JR; Department of Chemistry and Biochemistry, University of Nevada -Las Vegas, 4505 S. Maryland Pkwy, Las Vegas, NV, 89154, USA., Yip C; Department of Chemistry and Biochemistry, University of Nevada -Las Vegas, 4505 S. Maryland Pkwy, Las Vegas, NV, 89154, USA., Sharma PV; Department of Pharmaceutical Sciences, Eugene Applebaum College of Pharmacy and Health Sciences, Wayne State University, 259 Mack Avenue, Detroit, MI, 48201, USA., Abel-Santos E; Department of Chemistry and Biochemistry, University of Nevada -Las Vegas, 4505 S. Maryland Pkwy, Las Vegas, NV, 89154, USA., Firestine SM; Department of Pharmaceutical Sciences, Eugene Applebaum College of Pharmacy and Health Sciences, Wayne State University, 259 Mack Avenue, Detroit, MI, 48201, USA. Electronic address: sfirestine@wayne.edu.
Jazyk: angličtina
Zdroj: European journal of medicinal chemistry [Eur J Med Chem] 2023 Dec 05; Vol. 261, pp. 115788. Date of Electronic Publication: 2023 Sep 04.
DOI: 10.1016/j.ejmech.2023.115788
Abstrakt: Clostridioides difficile infection (CDI) is a major identifiable cause of antibiotic-associated diarrhea. In our previous study (J. Med. Chem., 2018, 61, 6759-6778), we have identified N-phenyl-cholan-24-amide as a potent inhibitor of spore germination. The most potent compounds in our previous work are N-arylamides. We were interested in the role that the conformation of the amide plays in activity. Previous research has shown that secondary N-arylamides exist exclusively in the coplanar trans conformation while tertiary N-methyl-N-arylamides exist in a non-planar, cis conformation. The N-methyl-N-phenyl-cholan-24-amide was 17-fold less active compared to the parent compounds suggesting the importance of the orientation of the phenyl ring. To lock the phenyl ring into a trans conformation, cyclic tertiary amides were prepared. Indoline and quinoline cholan-24-amides were both inhibitors of spore germination; however, the indoline analogs were most potent. Isoindoline and isoquinoline amides were inactive. We found that the simple indoline derivative gave an IC 50 value of 1 μM, while the 5'-fluoro-substituted compound (5d) possessed an IC 50 of 400 nM. To our knowledge, 5d is the most potent known spore germination inhibitor described to date. Taken together, our results indicate that the trans, coplanar conformation of the phenyl ring is required for potent inhibition.
Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Steven Firestine and Ernesto Abel-Santos report financial support was provided by National Institutes of Health. The authors have a patent pending on these compounds. E. Abel-Santos has established a company Abel Therapeutics.
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Databáze: MEDLINE
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