Details

Autor(en) / Beteiligte

• Sharma, Shiv K.
• Schilke, Angel R.
• Phan, Jacqueline R.
• Yip, Christopher
• Sharma, Prateek V.
• Abel-Santos, Ernesto
• Firestine, Steven M.

Titel

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

Ist Teil von

• European journal of medicinal chemistry, 2023-12, Vol.261, p.115788-115788, Article 115788

Ort / Verlag

Elsevier Masson SAS

Erscheinungsjahr

2023

Link zum Volltext

Quelle

Elsevier ScienceDirect Journals Complete

Beschreibungen/Notizen

• 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 IC50 value of 1 μM, while the 5′-fluoro-substituted compound (5d) possessed an IC50 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. [Display omitted] •C. difficile spore germination is required for disease.•N-5′-fluoroindoline-cholan-24-amide (5d) inhibits germination (IC50 of 400 nM).•5d is the most potent spore germination inhibitor described to date.•The trans, coplanar conformation of the phenyl ring results in potent inhibition.