Stoyanova Savina, Bogdanov Milen G
Faculty of Chemistry and Pharmacy, Sofia University St. Kliment Ohridski, 1, Jammes Bourchier Blvd., 1164 Sofia, Bulgaria.
Molecules. 2025 Feb 6;30(3):735. doi: 10.3390/molecules30030735.
This study investigates heterocyclic gamma-butyrobetaine (GBB) analogs as metabolic modulators through an integrated approach involving rational design, molecular docking, synthesis, and in vitro evaluation. The compounds synthesized demonstrated promising inhibitory potential toward carnitine acetyltransferase (CAT) and presumably other enzymes within the carnitine transferase family, with IC values ranging from 2.24 to 43.6 mM. Notably, some compounds demonstrated superior activity to the reference drug Meldonium (IC = 11.39 mM). A substantial outcome of the study that might serve as a foundation for future optimization and synthesis of more potent compounds was that a bulky, hydrophobic substituent at the gamma position enhances inhibitory activity, whereas esterification and increased polarity diminish it. The most effective compound was determined to be a reversible competitive inhibitor of CAT, with a value of 3.5 mM comparable to Meldonium's of 1.63 mM. These results suggest that heterocyclic GBB analogs present potential candidates for regulating metabolic processes and treating conditions including ischemic diseases, diabetes, and specific cancers.
本研究通过一种综合方法，包括合理设计、分子对接、合成和体外评估，来研究杂环γ-丁甜菜碱（GBB）类似物作为代谢调节剂的情况。合成的化合物对肉碱乙酰转移酶（CAT）以及推测的肉碱转移酶家族中的其他酶显示出有前景的抑制潜力，IC值范围为2.24至43.6 mM。值得注意的是，一些化合物表现出比参考药物美多心安（IC = 11.39 mM）更优异的活性。该研究的一个重要结果可能为未来更有效化合物的优化和合成奠定基础，即γ位上的一个庞大疏水取代基会增强抑制活性，而酯化和极性增加则会使其减弱。最有效的化合物被确定为CAT的可逆竞争性抑制剂，其Ki值为3.5 mM，与美多心安的1.63 mM相当。这些结果表明，杂环GBB类似物是调节代谢过程以及治疗包括缺血性疾病、糖尿病和特定癌症在内的病症的潜在候选物。
