Membrane effects of dihydropyrimidine analogues with larvicidal activity

MARIELA SÁNCHEZ-BORZONE; MARIANI, ELISA; MIGUEL VIRGINIA; GLEISER RAQUEL; ODHAV BARTHI; KATHARIGATTA VENUGOPALA; GARCIA, DANIEL

COLLOIDS AND SURFACES B-BIOINTERFACES

ELSEVIER SCIENCE BV

Lugar: Amsterdam; Año: 2017 vol. 150 p. 106 - 113

0927-7765

Two recently synthesized dihydropyrimidines (DHPMs) analogues have demonstrated larvicide andrepellent activity against Anopheles arabiensis. DHPMs high lipophilicity suggests that these compoundsmay interact directly with the membrane and modify their biophysical properties. The purpose of thepresent study was to characterize the interaction of both compounds with artificial membranes. Changeson the properties of DPPC films were studied using Langmuir monolayers. The presence of DHPMs in thesubphase modified the interfacial characteristics of DPPC compression isotherms, causing the expansionof the monolayer, inducing the disappearance of DPPC phase transition and increasing the molecularpacking of the film. Moreover, both compounds showed ability to penetrate into the lipid monolayersat molecular pressures comparable to those in biological membranes. The effects of both DHPMs onthe molecular organization of DPPC liposomes were measured by fluorescence anisotropy. The resultsindicate that their presence between lipid molecules would induce an increasing intermolecular interac-tion, diminishing the bilayer fluidity mainly at the polar region. Finally, we performed free diffusion MDsimulations and obtained spatially resolved free energy profiles of DHPMs partition into a DPPC bilayerthrough Potential of Mean Force (PMF) calculations. In agreement with the experimental assays, PMF pro-files and MD simulations showed that DHPMs are able to partition into DPPC bilayers, penetrating into themembrane and stablishing hydrogen bonds with the carbonyl moiety. Our results suggest that DHPMsbioactivity could involve their interaction with the lipid molecules that modulate the supramolecularorganization of the biological membranes and consequently the membrane proteins functionality