Rational Design, Synthesis, and In Vitro Activity of Heterocyclic Gamma-Butyrobetaines as Potential Carnitine Acetyltransferase Inhibitors

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 IC50 values ranging from 2.24 to 43.6 mM. Notably, some compounds demonstrated superior activity to the reference drug Meldonium (IC50 = 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 Ki value of 3.5 mM comparable to Meldonium’s Ki 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.