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

摘要

The 2‐amine derivatives of 5‐arylidene‐3 H ‐imidazol‐4(5 H )‐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‐3 H ‐imidazol‐4(5 H )‐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]‐3 H ‐imidazol‐4(5 H )‐one, ( 3 ), two different salts were prepared, namely with picolinic acid {systematic name: 4‐[( Z )‐4‐(4‐chlorobenzylidene)‐5‐oxo‐3,4‐dihydro‐1 H ‐imidazol‐2‐yl]‐1‐(2‐hydroxyethyl)piperazin‐1‐ium pyridine‐2‐carboxylate, C 16 H 20 ClN 4 O 2 + ·C 6 H 4 NO 2 ? , ( 3 a )} and 4‐nitrophenylacetic acid {systematic name: 4‐[( Z )‐4‐(4‐chlorobenzylidene)‐5‐oxo‐3,4‐dihydro‐1 H ‐imidazol‐2‐yl]‐1‐(2‐hydroxyethyl)piperazin‐1‐ium 2‐(4‐nitrophenyl)acetate, C 16 H 20 ClN 4 O 2 + ·C 8 H 6 NO 4 ? , ( 3 b )}. 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 ( 3 a )] and C—H…O [in ( 3 a ) and ( 3 b )] 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 3 H ‐imidazol‐4(5 H )‐one [systematic name: 1 H ‐imidazol‐5(4 H )‐one], is also that most frequently observed in other structures containing this heterocycle.