Conformational study of (Z)-5-(4-chlorobenzylidene)-2-[4-(2-hydroxyethyl)piperazin-1-yl]-3H-imidazol-4(5H)-one in different environments: insight into the structural properties of bacterial efflux pump inhibitors.

Abstract

The 2-amine derivatives of 5-arylidene-3H-imidazol-4(5H)-one are a new class of bacterial efflux pump inhibitors, the chemical compounds that are able to restore antibiotic efficacy against multidrug resistant bacteria. 5-Arylidene-3H-imidazol-4(5H)-ones with a piperazine ring at position 2 reverse the mechanisms of multidrug resistance (MDR) of the particularly dangerous Gram-negative bacteria E. coli by inhibition of the efflux pump AcrA/AcrB/TolC (a main multidrug resistance mechanism in Gram-negative bacteria, consisting of a membrane fusion protein, AcrA, a Resistant-Nodulation-Division protein, AcrB, and an outer membrane factor, TolC). In order to study the influence of the environment on the conformation of (Z)-5-(4-chlorobenzylidene)-2-[4-(2-hydroxyethyl)piperazin-1-yl]-3H-imidazol-4(5H)-one, (3), two different salts were prepared, namely with picolinic acid {systematic name: 4-[(Z)-4-(4-chlorobenzylidene)-5-oxo-3,4-dihydro-1H-imidazol-2-yl]-1-(2-hydroxyethyl)piperazin-1-ium pyridine-2-carboxylate, C16H20ClN4O2+·C6H4NO2-, (3a)} and 4-nitrophenylacetic acid {systematic name: 4-[(Z)-4-(4-chlorobenzylidene)-5-oxo-3,4-dihydro-1H-imidazol-2-yl]-1-(2-hydroxyethyl)piperazin-1-ium 2-(4-nitrophenyl)acetate, C16H20ClN4O2+·C8H6NO4-, (3b)}. The crystal structures of the new salts were determined by X-ray diffraction. In both crystal structures, the molecule of (3) is protonated at an N atom of the piperazine ring by proton transfer from the corresponding acid. The carboxylate group of picolinate engages in hydrogen bonds with three molecules of the cation of (3), whereas the carboxylate group of 4-nitrophenylacetate engages in hydrogen bonds with only two molecules of (3). As a consequence of these interactions, different orientations of the hydroxyethyl group of (3) are observed. The crystal structures are additionally stabilized by both C-H...N [in (3a)] and C-H...O [in (3a) and (3b)] intermolecular interactions. The geometry of the imidazolone fragment was compared with other crystal structures possessing this moiety. The tautomer observed in the crystal structures presented here, namely 3H-imidazol-4(5H)-one [systematic name: 1H-imidazol-5(4H)-one], is also that most frequently observed in other structures containing this heterocycle.