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

This study examined heterocyclic gamma-butyrobetaine (GBB) analogs as metabolic modulators through rational design, docking, synthesis, and in vitro analyses. The compounds inhibited carnitine acetyltransferase (CAT) and possibly other enzymes in the carnitine transferase family, showing inhibitory potential in the low millimolar range (IC50 = 2.24–43.6 mM), with some more active than the well-known drug Meldonium (IC50 = 11.39 mM). Key findings include that bulky and hydrophobic substituent at the gamma-position enhances inhibition, while esterification and increased polarity reduce it. The most active compound was identified as a reversible competitive inhibitor of CAT, with a Ki value of 3.5 mM, similar to Meldonium’s Ki of 1.63 mM. These results indicate that heterocyclic GBB analogs are potential candidates for regulating metabolic processes and for treating conditions such as ischemic diseases, diabetes, and certain cancers.