Experimental and computational analysis of lipophilicity and plasma protein binding properties of potent tacrine based cholinesterase inhibitors

Abstract

The lipophilicity of thirteen tacrine/piperidine-4-carboxamide derivatives was assessed using reversed-phase thin-layer chromatography (RP-TLC) with MeOH and acetonitrile (ACN) as organic modifiers. Among the parameters evaluated, the R_M⁰ and C⁰ values obtained using MeOH were identified as the most reliable for characterizing the lipophilicity of the investigated compounds. The observed differences in lipophilicity among the derivatives resulted from a delicate interplay of substituent effects (hydrophobicity, polarity, steric hindrance, and electronic effects), positional influence, and characteristics of the organic modifier.

The plasma protein-binding (PPB) properties of the tacrine derivatives were analyzed using an HPLC method with a human serum albumin (HSA) stationary phase and a mobile phase composed of phosphate buffer (pH = 7) and 2-propanol. The experimental %PPB values calculated using from two experiments ranged from 82.38 % to 94.54 %, and 84.29 % to 98.16 % suggesting that most compounds bind efficiently but not excessively to plasma proteins.

Docking analysis revealed that all investigated ligands bind to Sudlow site I within HSA, which is the main binding site for heterocyclic aromatic compounds such as warfarine, azoprazone and tacrine. The key binding interactions are primarily hydrogen bonding and aromatic interactions.

Principal component analysis (PCA), conducted on both experimentally determined and predicted lipophilicity values, as well as on predicted adsorption and experimentally and predicted distribution data, underscored the significant role of lipophilicity in influencing adsorption and distribution processes.