Department of Pharmaceutical sciences, Eugene Applebaum College of Pharmacy and Health Sciences, Wayne State University, 259 Mack Avenue, Detroit, MI 48201, United States.
Department of Chemistry and Biochemistry, University of Nevada at Las Vegas, 4505 S. Maryland Pkwy., Las Vegas, NV, 89154, United States.
Bioorg Med Chem. 2021 Dec 15;52:116503. doi: 10.1016/j.bmc.2021.116503. Epub 2021 Nov 10.
Chenodeoxycholic acid (CDCA) is a natural germination inhibitor for C. difficile spores. In our previous study (J. Med. Chem., 2018, 61, 6759-6778), we identified N-phenyl-3α,7α,12α-trihydroxy-5β-cholan-24-amide as an inhibitor of C. difficile strain R20291 with an IC of 1.8 μM. Studies of bile salts on spore germination have shown that chenodeoxycholate, ursodeoxycholate and lithocholate are more potent inhibitors of germination compared to cholate. Given this, we created amide analogs of chenodeoxycholic, deoxycholic, lithocholic and ursodeoxycholic acids using amines identified from our previous studies. We found that chenodeoxy- and deoxycholate derivatives were active with potencies equivalent to those for cholanamides. This indicates that only 2 out of the 3 hydroxyl groups are needed for activity and that the alpha stereochemistry at position 7 is required for inhibition of spore germination.
鹅去氧胆酸（CDCA）是艰难梭菌孢子的天然发芽抑制剂。在我们之前的研究（J. Med. Chem.，2018，61，6759-6778）中，我们确定 N-苯基-3α，7α，12α-三羟基-5β-胆烷-24-酰胺是艰难梭菌 R20291 的抑制剂，IC 为 1.8 μM。对胆盐对孢子发芽的研究表明，与胆酸盐相比，鹅去氧胆酸盐、熊去氧胆酸盐和石胆酸盐是更有效的发芽抑制剂。有鉴于此，我们使用之前研究中鉴定的胺类物质，合成了鹅去氧胆酸、脱氧胆酸、石胆酸和熊去氧胆酸的酰胺类似物。我们发现，鹅去氧胆酸盐和脱氧胆酸盐衍生物具有与胆烷酰胺相当的活性。这表明只有 3 个羟基中的 2 个需要活性，并且位置 7 的α立体化学需要抑制孢子发芽。
