What question did this study set out to answer?

This research aims to enhance the oral absorption of albendazole by conjugating it with cholic acid, utilizing a biocatalytic approach.

May 1, 2026Catalysts0 citationsOpen Access

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

SSShuyi ShangChinese Academy of Sciences JLJiahao LiuBeijing University of Chemical Technology JLJingshuai LiuBeijing University of Chemical Technology

Key Points

This research aims to enhance the oral absorption of albendazole by conjugating it with cholic acid, utilizing a biocatalytic approach.
Synthesis of ABZ-linker-CA conjugates with varying linker lengths (C4-C8) was performed, assessing yield and performance.
Immobilized lipase Lipozyme RM IM was screened for effectiveness in catalyzing cholic acid esterification.
Ex vivo transport studies evaluated the conjugates' uptake via the apical sodium-dependent bile acid transporter.
The best performing conjugate, ABZ-C6-CA, showed an optimal balance of uptake and efficacy, enabling high ASBT-mediated absorption.
Linker-length dependence was noted with yields of 31% for C4, 25% for C6, and ≤2.6% for C8.
Protoscolex assays demonstrated that ABZ-C6-CA had improved antiparasitic efficacy compared to albendazole alone.

Abstract

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.

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