Lipid Matters: How Herbicidal Ionic Liquids Engage with Membranes

This study explores the influence of alkyl chain length and concentration of herbicidal ionic liquids based on (4-chloro-2-methylphenoxy)acetic acid (MCPA) on the structural and mechanical properties of model lipid monolayers composed of phospholipids: 1,2-dimyristoyl-<i>sn</i>-glycero-3-phosphoethanolamine (DMPE), 1,2-dipalmitoyl-<i>sn</i>-glycero-3-phosphocholine (DPPC), and sterols (cholesterol, ergosterol). Using the Langmuir monolayer technique, we demonstrate that the effects of [Cn][MCPA] on lipid films strongly depend on both the alkyl chain length and the herbicide concentration. Among the studied compounds, ionic liquids with dodecyl and tetradecyl chains exhibited the most pronounced fluidizing and expanding effects. Dose-dependent experiments revealed that increasing [C12][MCPA] concentrations enhance monolayer expansion and fluidization, with magnitudes varying across lipid types. Penetration experiments simulating dynamic herbicide-membrane interactions indicate a substantial ability of [C12][MCPA] to insert into condensed DMPE and ergosterol monolayers, while insertion into cholesterol and DPPC films is limited. The diverse responses of lipid membranes to [C12][MCPA] suggest the potential to modulate herbicide selectivity toward target and nontarget cell membranes, thereby improving both efficacy and environmental safety. Overall, our findings elucidate key structure-activity relationships governing membrane perturbation by herbicidal ionic liquids and validate Langmuir monolayer studies as an efficient in vitro approach for predicting the biological activity of membrane perturbants. This work provides molecular-level insights that can guide the rational design of selective and safe herbicidal agents.