Imidazolidine-4-one derivatives in the search for novel chemosensitizers of Staphylococcus aureus MRSA: Synthesis, biological evaluation and molecular modeling studies

Matys, Anna; Podlewska, Sabina; Witek, Karolina; Witek, Jagna; Bojarski, Andrzej J.; Schabikowski, Jakub; Otrębska-Machaj, Ewa; Latacz, Gniewomir; Szymańska, Ewa; Kieć‐Kononowicz, Katarzyna; Molnár, Joséph; Amaral, Leonard; Handzlik, Jadwiga

doi:10.1016/j.ejmech.2015.06.013

Cited by 25 publications

(28 citation statements)

References 29 publications

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“…5-arylidenehydantoins (Handzlik et al, 2013;Spengler et al, 2010) or 5-arylideneimidzol-4-ones (Bohnert et al, 2016), are a very promising group. These compounds are able to block MDR efflux pumps (Amaral et al, 2012) or act as adjuvants of antibiotics also via other mechanisms (Matys et al, 2015). The results of our previous studies indicate that both efflux pump inhibitory potency and pump specificity were significantly affected by the presence and position of a piperazine moiety within the molecules.…”

Section: Introductionmentioning

confidence: 63%

“…However, much better properties with regard to adjuvants of antibiotics were achieved with the introduction of the piperazine substituent at the 2-position converting, along the way, imidazolidine-2,4-dione into imidazole-4-one [(3) and (4) in Fig. 1] (Bohnert et al, 2016;Matys et al, 2015). Thus, the last group [(3) and 4], represented also by compounds (5) and (6) ( Fig.…”

Section: Introductionmentioning

confidence: 99%

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Influence of 3-{5-[4-(diethylamino)benzylidene]rhodanine}propionic acid on the conformation of 5-(4-chlorobenzylidene)-2-(4-methylpiperazin-1-yl)-3H-imidazol-4(5H)-one

et al. 2018

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The arylidene–imidazolone derivatives are a group of compounds of great interest in medicinal chemistry due to their various pharmacological actions. In order to study the possible conformations of an arylidene–imidazolone derivative, two new crystal structures were determined by X‐ray diffraction, namely (Z)‐5‐(4‐chlorobenzylidene)‐2‐(4‐methylpiperazin‐1‐yl)‐3H‐imidazol‐5(4H)‐one, C15H17ClN4O, (6), and its salt 4‐[5‐(4‐chlorobenzylidene)‐5‐oxo‐4,5‐dihydro‐3H‐imidazol‐2‐yl]‐1‐methylpiperazin‐1‐ium 3‐{5‐[4‐(diethylamino)benzylidene]‐4‐oxo‐2‐thioxothiazolidin‐3‐yl}propionate, C15H18ClN4O+·C17H19N2O3S2−, (7). Both compounds crystallize in the space group P. The basic form (6) crystallizes with two molecules in the asymmetric unit. In the acid form of (6), the N atom of the piperazine ring is protonated by proton transfer from the carboxyl group of the rhodanine acid derivative. The greatest difference in the conformations of (6) and its protonated form, (6c), is observed in the location of the arylidene–imidazolone substituent at the N atom. In the case of (6c), the position of this substituent is close to axial, while for (6), the corresponding position is intermediate between equatorial and axial. The crystal packing is dominated by a network of N—H…O hydrogen bonds. Furthermore, the crystal structures are stabilized by numerous intermolecular contacts of types C—H…N and C—H…Cl in (6), and C—H…O and C—H…S in (7). The geometry with respect to the location of the substituents at the N atoms of the piperazine ring was compared with other crystal structures possessing an N‐methylpiperazine moiety.

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Section: Introductionmentioning

confidence: 63%

Section: Introductionmentioning

confidence: 99%

Influence of 3-{5-[4-(diethylamino)benzylidene]rhodanine}propionic acid on the conformation of 5-(4-chlorobenzylidene)-2-(4-methylpiperazin-1-yl)-3H-imidazol-4(5H)-one

et al. 2018

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“…Hydantoin derivatives used in the pharmacological assays were obtained by chemical synthesis. The new generations IIIA and B were obtained using 3–4-step synthesis ( Handzlik et al, 2014 ; Matys et al, 2015 ; Figure 1 and Supplementary data). Purity and identity of new compounds were confirmed using spectral analysis (H-NMR, IR), elemental analysis and melting point measurements.…”

Section: Methodsmentioning

confidence: 99%

Efflux Pump Blockers in Gram-Negative Bacteria: The New Generation of Hydantoin Based-Modulators to Improve Antibiotic Activity

et al. 2016

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Multidrug resistant (MDR) bacteria are an increasing health problem with the shortage of new active antibiotic agents. Among effective mechanisms that contribute to the spread of MDR Gram-negative bacteria are drug efflux pumps that expel clinically important antibiotic classes out of the cell. Drug pumps are attractive targets to restore the susceptibility toward the expelled antibiotics by impairing their efflux activity. Arylhydantoin derivatives were investigated for their potentiation of activities of selected antibiotics described as efflux substrates in Enterobacter aerogenes expressing or not AcrAB pump. Several compounds increased the bacterial susceptibility toward nalidixic acid, chloramphenicol and sparfloxacin and were further pharmacomodulated to obtain a better activity against the AcrAB producing bacteria.

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“…vants of -lactam antibiotics (oxacillin and cloxacillin) against S. aureus strains (HEMSA), the highly problematic Grampositive bacteria in clinical treatment (Matys et al, 2015). Both actions are very promising for a new therapeutic approach to the treatment of bacterial infections.…”

Section: Figurementioning

confidence: 99%

“…1b], but a series of more promising agents was found in the group of 5-arylidene-substituted hydantoins, modification pathway (II), with piperazine at position 3 [(2); Fig. 1b] (Handzlik et al, 2012) strongly improved the activity (Bohnert et al, 2016;Matys et al, 2015). Further modifications in order to change the imidazolidine-2,4-dione core into 3H-imidazol-4(5H)-one [modification pathway (III); Fig.…”

Section: Introductionmentioning

confidence: 99%

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

2017

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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, CHClNO·CHNO, (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, CHClNO·CHNO, (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.

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Imidazolidine-4-one derivatives in the search for novel chemosensitizers of Staphylococcus aureus MRSA: Synthesis, biological evaluation and molecular modeling studies

Cited by 25 publications

References 29 publications

Influence of 3-{5-[4-(diethylamino)benzylidene]rhodanine}propionic acid on the conformation of 5-(4-chlorobenzylidene)-2-(4-methylpiperazin-1-yl)-3H-imidazol-4(5H)-one

Influence of 3-{5-[4-(diethylamino)benzylidene]rhodanine}propionic acid on the conformation of 5-(4-chlorobenzylidene)-2-(4-methylpiperazin-1-yl)-3H-imidazol-4(5H)-one

Efflux Pump Blockers in Gram-Negative Bacteria: The New Generation of Hydantoin Based-Modulators to Improve Antibiotic Activity

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

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