Molecular Imprinting of Benzylpiperazine: A Comparison of the Self-Assembly and Semi-Covalent Approaches.

Molecularly imprinted polymers (MIPs) for benzylpiperazine (BZP, 1 ), an illicit designer drug, were developed by using both self-assembly and semi-covalent approaches. From an array of potential functional monomers (FMs) and using a combination of pre-synthetic interaction studies (by molecular modelling and NMR analysis) and binding assays, the highest performing self-assembly 1 -MIPs were confirmed to result from methacrylic acid ( 7 ) as FM, ethylene glycol dimethacrylate (EGDMA) or trimethylolpropane trimethacrylate (TRIM) as crosslinkers and chloroform as the porogen and rebinding solvent at template (T): FM ratios of 1:1 and 1:2, giving imprinting factors (IF) 3 to 7. The semi-covalent 1 -MIPs were designed using benzylpiperazine (4-vinylphenyl) carbamate ( 16 ) as the template-monomer adduct in combination with either EDGMA or TRIM. Our comparative analysis showed the semi-covalent polymers to have a stronger affinity for 1 (significantly lower K d values and higher IFs) and faster uptake than the self-assembly systems. Both approaches have comparable cross-reactivity: marginal to low against cocaine ( 17 ) and morphine ( 18 ) and high against ephedrine ( 19 ) and phenylpiperazine ( 20 ). They also have comparable selectivity: highly selective towards 1 against 17 , moderate against 18 and non-selective against 19 . EGDMA-based self-assembly MIPs displayed a greater imprinting effect (higher IFs and NIP-to-MIP K d ratios) than TRIM-based MIPs, while the TRIM-based semi-covalent MIP outperformed its EGDMA-based equivalent. By virtue of its modest selectivity against the test illicit drugs, 1 -MIPs could potentially be used as a dummy MIP for the broad-based capture and enrichment of illicit drug blends for subsequent laboratory analysis.