Chemoenzymatic Two-Step Synthesis of Albendazole–Cholic Acid Conjugates: Linker-Length-Controlled Biocatalytic Esterification

Albendazole (ABZ) exhibits poor oral absorption; therefore, ABZ was conjugated to cholic acid to engage the apical sodium-dependent bile acid transporter (ASBT) and promote ileal uptake. ABZ–linker–CA conjugates bearing amino-alcohol linkers (C4–C8) were evaluated by integrating synthetic feasibility, purification selectivity, and ex vivo performance. Thermal aminolysis in DMF (95 °C) produced ABZ–linkers in ~50% reaction yields (HPLC-assayed), with a minor ABZ-amine by-product consistent with a workup-sensitive isocyanate route. Immobilized-lipase screening identified Lipozyme RM IM as the most effective catalyst for CA esterification in CHCl3, showing a pronounced linker-length dependence (31% yield for C4, 25% for C6, and C8 ≤ 2.6% yield). Docking and molecular dynamics supported this trend by indicating productive binding geometries for C4/C6 but not for C8. A polarity-guided workup and silica-gel protocol enabled retrieval of unreacted intermediates and CA recycling, with cleaner separation for the C6 series. Ex vivo transport studies confirmed ASBT-mediated, linerixibat-sensitive ileal uptake, and protoscolex assays showed improved antiparasitic efficacy versus ABZ. Overall, ABZ-C6-CA offered the best balance of uptake, near-maximal efficacy, enzymatic accessibility, and separability, supporting its prioritization for scalable biocatalytic manufacturing.