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1.
Int J Mol Sci ; 22(4)2021 Feb 19.
Article in English | MEDLINE | ID: mdl-33669790

ABSTRACT

In the search for an effective strategy to overcome antimicrobial resistance, a series of new morpholine-containing 5-arylideneimidazolones differing within either the amine moiety or at position five of imidazolones was explored as potential antibiotic adjuvants against Gram-positive and Gram-negative bacteria. Compounds (7-23) were tested for oxacillin adjuvant properties in the Methicillin-susceptible S. aureus (MSSA) strain ATCC 25923 and Methicillin-resistant S. aureus MRSA 19449. Compounds 14-16 were tested additionally in combination with various antibiotics. Molecular modelling was performed to assess potential mechanism of action. Microdilution and real-time efflux (RTE) assays were carried out in strains of K. aerogenes to determine the potential of compounds 7-23 to block the multidrug efflux pump AcrAB-TolC. Drug-like properties were determined experimentally. Two compounds (10, 15) containing non-condensed aromatic rings, significantly reduced oxacillin MICs in MRSA 19449, while 15 additionally enhanced the effectiveness of ampicillin. Results of molecular modelling confirmed the interaction with the allosteric site of PBP2a as a probable MDR-reversing mechanism. In RTE, the compounds inhibited AcrAB-TolC even to 90% (19). The 4-phenylbenzylidene derivative (15) demonstrated significant MDR-reversal "dual action" for ß-lactam antibiotics in MRSA and inhibited AcrAB-TolC in K. aerogenes. 15 displayed also satisfied solubility and safety towards CYP3A4 in vitro.


Subject(s)
Anti-Bacterial Agents/pharmacology , Drug Resistance, Multiple, Bacterial/genetics , Imidazoles/pharmacology , Morpholines/pharmacology , Allosteric Site , Anti-Bacterial Agents/chemical synthesis , Anti-Bacterial Agents/chemistry , Bacteria/drug effects , Crystallography, X-Ray , Drug Evaluation, Preclinical , Drug Interactions , Drug Resistance, Multiple, Bacterial/drug effects , Hydrogen Bonding , Hydrogen-Ion Concentration , Imidazoles/chemical synthesis , Imidazoles/chemistry , Ligands , Microbial Sensitivity Tests , Molecular Conformation , Molecular Docking Simulation , Morpholines/chemical synthesis , Morpholines/chemistry , Solubility , Structure-Activity Relationship , Water
2.
Molecules ; 24(3)2019 Jan 26.
Article in English | MEDLINE | ID: mdl-30691112

ABSTRACT

Searching for new chemosensitizers of bacterial multidrug resistance (MDR), chemical modifications of (Z)-5-(4-chlorobenzylidene)-2-(4-methylpiperazin-1-yl)-3H-imidazol-4(5H)-one (6) were performed. New compounds (7⁻17), with fused aromatic rings at position 5, were designed and synthesized. Crystallographic X-ray analysis proved that the final compounds (7⁻17) were substituted with tertiary amine-propyl moiety at position 3 and primary amine group at 2 due to intramolecular Dimroth rearrangement. New compounds were evaluated on their antibiotic adjuvant properties in either Gram-positive or Gram-negative bacteria. Efflux pump inhibitor (EPI) properties towards the AcrAB-TolC pump in Enterobacter aerogenes (EA289) were investigated in the real-time efflux (RTE) assay. Docking and molecular dynamics were applied to estimate an interaction of compounds 6⁻17 with penicillin binding protein (PBP2a). In vitro ADME-Tox properties were evaluated for compound 9. Most of the tested compounds reduced significantly (4-32-fold) oxacillin MIC in highly resistant MRSA HEMSA 5 strain. The anthracene-morpholine derivative (16) was the most potent (32-fold reduction). The tested compounds displayed significant EPI properties during RTE assay (37⁻97%). The naphthyl-methylpiperazine derivative 9 showed the most potent "dual action" of both oxacillin adjuvant (MRSA) and EPI (E. aerogenes). Molecular modeling results suggested the allosteric mechanism of action of the imidazolones, which improved binding of oxacillin in the PBP2a active site in MRSA.


Subject(s)
Amines/chemistry , Anti-Bacterial Agents/chemistry , Anti-Bacterial Agents/pharmacology , Drug Resistance, Multiple, Bacterial/drug effects , Imidazoles/chemistry , Imidazoles/pharmacology , Bacteria/drug effects , Bacteria/genetics , Bacteria/metabolism , Bacterial Proteins/chemistry , Bacterial Proteins/metabolism , Humans , Hydrogen Bonding , Microbial Sensitivity Tests , Models, Molecular , Molecular Structure , Structure-Activity Relationship
3.
Expert Opin Drug Metab Toxicol ; 13(3): 301-309, 2017 Mar.
Article in English | MEDLINE | ID: mdl-27764576

ABSTRACT

INTRODUCTION: Worrying levels of bacterial resistance have been reported worldwide involving the failure of many available antibiotic treatments. Multidrug resistance (MDR) in Gram-negative bacteria is often ascribed to the presence of multiple and different resistance mechanisms in the same strain. RND efflux pumps play a major role and are an attractive target to discover new antibacterial drugs. Areas covered: This review discusses the prevalence of efflux pumps, their overexpression in clinical scenarios, their polyselectivity, their effect on the intracellular concentrations of various antibiotics associated with the alteration of the membrane permeability and their involvement in pathogenicity are discussed. Expert opinion: Efflux pumps are new targets for the development of adjuvant in antibiotic treatments by of efflux pump inhibition. They may allow us to rejuvenate old antibiotics acting on their concentration inside the bacteria and thus potentiating their activity while blocking the release of virulence factors. It is a pharmacodynamic challenge to finalize new combined therapy.


Subject(s)
Anti-Bacterial Agents/pharmacology , Gram-Negative Bacterial Infections/drug therapy , Membrane Transport Proteins/metabolism , Anti-Bacterial Agents/administration & dosage , Drug Design , Drug Resistance, Multiple, Bacterial , Gram-Negative Bacteria/drug effects , Gram-Negative Bacterial Infections/microbiology , Humans
4.
Front Microbiol ; 7: 622, 2016.
Article in English | MEDLINE | ID: mdl-27199950

ABSTRACT

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.

5.
Bioorg Med Chem ; 21(1): 135-45, 2013 Jan 01.
Article in English | MEDLINE | ID: mdl-23218781

ABSTRACT

A series of amine-alkyl derivatives of 5-arylidenehydantoin 3-21 was evaluated for their ability to improve antibiotic effectiveness in two strains of Gram-negative Enterobacter aerogenes: the reference strain (ATCC-13048) and the chloramphenicol-resistant derivative over-producing the AcrAB-TolC efflux pump (CM-64). Three antibiotics, chloramphenicol, nalidixic acid and sparfloxacin were used as markers of efflux pump activity. New compounds (5-16) were obtained within 3-4 step synthesis using Knoevenagel condensation, Mitsunobu reaction and microwave aided N-alkylation. Molecular modeling based structure-activity relationship (SAR) studies were performed. The most active compounds: (Z)-5-(4-(diethylamino)benzylidene)-3-(2-hydroxy-3-(4-(2-hydroxyethyl)piperazin-1-yl)propyl)imidazolidine-2,4-dione (14) and (Z)-5-(2,4-dimethoxybenzylidene)-3-(2-hydroxy-3-(isopropylamino)propyl)imidazolidine-2,4-dione (15) induced fourfold decrease of minimal inhibition concentration (MIC) of all tested antibiotics in the strain CM-64 overexpressing the AcrAB-TolC pump.


Subject(s)
Amines/pharmacology , Anti-Bacterial Agents/pharmacology , Drug Resistance, Multiple, Bacterial/drug effects , Enterobacter aerogenes/drug effects , Enterobacteriaceae Infections/drug therapy , Hydantoins/pharmacology , Amines/chemistry , Anti-Bacterial Agents/chemistry , Humans , Hydantoins/chemistry , Models, Molecular
6.
Eur J Med Chem ; 46(12): 5807-16, 2011 Dec.
Article in English | MEDLINE | ID: mdl-22000919

ABSTRACT

A series of new 5,5-diphenylhydantoin derivatives with various amine-alkyl terminal fragments at N1-position were synthesized. Then a series of twenty-eight compounds with the same hydantoin scaffold were evaluated for their potency to combat bacterial MultiDrug Resistance (MDR). Intrinsic antibacterial activities were first evaluated. As these compounds showed no direct activity on bacteria, their influence on minimal inhibitory concentration (MIC) of nalidixic acid was tested in two strains of Enterobacter aerogenes: the reference-strain ATCC-13048 and the CM-64 strain which over-produces AcrAB-TolC efflux pump. The compounds showed moderate- or low- anti-MDR properties. According to SAR-studies, hit compounds containing 2-methoxyphenylpiperazine at N1-terminal fragment and methylcarboxyl acid one at N3-position of hydantoin have been identified for further microbiological studies and pharmacomodulations to develop efflux pump inhibitors.


Subject(s)
Anti-Bacterial Agents/pharmacology , Drug Resistance, Multiple, Bacterial/drug effects , Enterobacter aerogenes/drug effects , Hydantoins/chemistry , Hydantoins/pharmacology , Nalidixic Acid/pharmacology , Amines/chemistry , Amines/pharmacology , Bacterial Proteins/antagonists & inhibitors , Bacterial Proteins/metabolism , Carrier Proteins/antagonists & inhibitors , Carrier Proteins/metabolism , Enterobacter aerogenes/metabolism , Enterobacteriaceae Infections/drug therapy , Humans , Microbial Sensitivity Tests , Structure-Activity Relationship
7.
Med Chem ; 4(5): 426-37, 2008 Sep.
Article in English | MEDLINE | ID: mdl-18782039

ABSTRACT

The capacity of ten molecules for reversing resistance in Plasmodium falciparum in vitro to quinoline antimalarial drugs, such as chloroquine (CQ), quinine (QN), mefloquine (MQ) and monodesethylamodiaquine (MDAQ), was assessed against 27 Plasmodium falciparum isolates. Four of these compounds were 9,10-dihydroethanoanthracene derivatives (DEAs). These DEAs reversed 75 to 92% of the CQ resistant strains. These synthetic compounds were more effective in combination with CQ than verapamil, ketotifen, chlorpromazine, reserpine or nicardipine, which reversed less than 50% of the CQ resistant strains. DEAs significantly reversed 67 to 100% of MDAQ resistant parasites. These compounds were more effective in combination with MDAQ than ketotifen (60% of reversal), chlorpromazine (45%), verapamil (33%), reserpine (30%) or nicardipine (9%). The reversal activity of MQ resistance was less pronounced, regardless of the molecule tested, and was homogeneous with a rate ranging from 42% for ketotifen to 58% for reserpine, nicardipine, verapamil and cyproheptadine. The four DEAs significantly reversed 50 to 55% of the parasites resistant to MQ. Fifty-six to 78 % of the QN resistant parasites were reversed by the synthetic DEAs. There were few differences in the rate of reversal activity on QN resistant strains between the ten compounds, with rates ranging between 56 to 78% for the ten chemosensitizers. The use of DEAs in combination with quinoline seems to be thus a promising strategy for limiting the development of drug resistant strains and for treating patients in drug resistant areas.


Subject(s)
Anthracenes/therapeutic use , Antimalarials/therapeutic use , Malaria, Falciparum/drug therapy , Plasmodium falciparum/drug effects , Quinolines/therapeutic use , Animals , Anthracenes/pharmacology , Antimalarials/pharmacology , Drug Resistance , Humans , Inhibitory Concentration 50 , Malaria, Falciparum/parasitology , Parasitic Sensitivity Tests , Plasmodium falciparum/growth & development , Quinolines/pharmacology , Structure-Activity Relationship
8.
Curr Top Med Chem ; 8(7): 563-78, 2008.
Article in English | MEDLINE | ID: mdl-18473883

ABSTRACT

Plasmodium falciparum is one of the most lethal parasite responsible for human malaria. Until now, the only one solution to counter malaria is the use of antimalarial drugs. Unfortunately, the extensively use of drugs, such as quinolines (i.e. chloroquine, quinine or mefloquine), have led to the emergence of drug resistance. Chloroquine and probably other quinolines act in interfering in the detoxification of hematin in the digestive vacuole. Quinolines are accumulated in P. falciparum digestive vacuole and the accumulation varies from a susceptible strain to a resistant one. Nevertheless, the mechanisms of quinoline resistance are still investigating. Genetic polymorphisms in some strains have been linked to drug resistance. The modifications observed are mutations on genes that encode transport proteins localized in the membrane of digestive vacuole. Three transporters were involved in quinoline resistance: PfCRT (Plasmodium falciparum chloroquine resistance transporter), Pgh1 (P-glycoprotein homologue 1) and PfMRP (Plasmodium falciparum multidrug resistance protein). They could be involved in accumulation or efflux mechanisms of drugs. In order to understand their role in resistance, localization, encoding gene structure, protein structure and endogenous function of these three transporters are reported. Some molecules that have no intrinsic antimalarial effect have been shown to reverse drug resistance when they are combined to chloroquine, quinine or mefloquine. These molecules are a solution to counter resistance but also they are precious tools to elucidate the resistance mechanisms. The molecules that have already shown a capacity to reverse chloroquine, quinine or mefloquine resistances were reported. Some of them could act on one of the three transporters involved in drug resistance, by confirming their role in quinoline resistance. Here we summarize the main elements of quinoline resistance and reversion of quinoline resistance related to malaria.


Subject(s)
Antimalarials/pharmacology , Carrier Proteins/metabolism , Drug Resistance/drug effects , Malaria, Falciparum/drug therapy , Plasmodium falciparum/drug effects , Quinolines/pharmacology , ATP-Binding Cassette Transporters/metabolism , Animals , Antimalarials/chemistry , Humans , Membrane Transport Proteins/metabolism , Plasmodium falciparum/metabolism , Protozoan Proteins/metabolism , Quinolines/metabolism
9.
Curr Drug Targets ; 7(8): 935-48, 2006 Aug.
Article in English | MEDLINE | ID: mdl-16918322

ABSTRACT

The development and spread of resistance to antimalarial drugs poses a severe and increasing public health threat. Failures of prophylaxis or treatment with quinolines, hydroxynaphthoquinones, sesquiterpene lactones, antifolate drugs and sulfamides are involved in a return malaria-related morbidity and mortality. Resistance is associated with a decrease in accumulation of drugs into the vacuole, which results from a reduced uptake of the drug, an increased efflux or a combination of both. A number of candidate genes in P. falciparum have been proposed to be involved in antimalarial resistance, each concerned in membrane transport. Weaker or stronger associations are seen in P. falciparum between the resistance to quinolines or artemisinin derivatives and codon changes in Pfmdr1, a gene which encodes Pgh-1, an ortholog of one of the P-glycoproteins expressed in multi-drug resistant human cancer cells (ABC transporter). Further analysis has revealed a new gene, Pfcrt, encoding a PfCRT protein, which resembles an anion channel. Codon changes found in the Pfcrt sequence in drug resistant isolates could facilitate the drug efflux through a putative channel. It has been proposed that the reversal of quinoline resistance by verapamil is due to hydrophobic binding to the mutated PfCRT protein. Several compounds have demonstrated in the past decade a promising capability to reverse the antimalarial drug resistance in vitro in parasite isolates, in animal models and in human malaria. These drugs belong to different pharmacological classes such as calcium channel blockers, tricyclic antidepressants, antipsychotic calmodulin antagonists, histamine H1-receptor antagonists, analgesic and antipyretic drugs, non-steroidal anti-inflammatory drugs, and to different chemical classes such as synthetic surfactants, alkaloids from plants used in traditional medicine, pyrrolidinoaminoalkanes and anthracenic derivatives. Here we summarize the progress made in biochemical and genetic basis of antimalarial resistance, emphasizing the recent developments on drugs, which interfere with trans membrane proteins involved in drug efflux or uptake.


Subject(s)
Antimalarials/therapeutic use , Chloroquine/therapeutic use , Drug Resistance/physiology , Animals , Antimalarials/chemistry , Antimalarials/pharmacology , Chloroquine/chemistry , Chloroquine/pharmacology , Drug Resistance/drug effects , Humans , Malaria, Falciparum/drug therapy , Membrane Proteins/physiology , Membrane Transport Proteins , Protozoan Proteins
10.
Antimicrob Agents Chemother ; 48(12): 4869-72, 2004 Dec.
Article in English | MEDLINE | ID: mdl-15561869

ABSTRACT

BG958 reverses resistance in chloroquine-resistant isolates from different countries. Five mutations in the Plasmodium falciparum crt (pfcrt) gene resulting in the amino acid changes K76T, M74I, N75E, A220S, and R371I are systematically identified in resistance-reversed Asian, African, and Brazilian parasites which possess the pfcrt (CIET) haplotype. In combination with BG958, the activity of chloroquine is increased in parasites with the N86Y mutation in pfmdr1.


Subject(s)
Anthracenes/pharmacology , Antimalarials/pharmacology , Carrier Proteins/genetics , Chloroquine/pharmacology , Plasmodium falciparum/genetics , Polymorphism, Genetic/genetics , Animals , DNA, Protozoan/genetics , DNA, Protozoan/isolation & purification , Drug Resistance , Drug Synergism , Genes, MDR/genetics , Humans , Malaria, Falciparum/parasitology , Membrane Proteins/genetics , Membrane Transport Proteins , Mutation/genetics , Plasmodium falciparum/drug effects , Plasmodium falciparum/metabolism , Protozoan Proteins , RNA, Protozoan/genetics , RNA, Protozoan/isolation & purification , Reverse Transcriptase Polymerase Chain Reaction
11.
Antimicrob Agents Chemother ; 48(7): 2753-6, 2004 Jul.
Article in English | MEDLINE | ID: mdl-15215144

ABSTRACT

The ability of four 9,10-dihydroethanoanthracene derivatives (BG920, BG932, BG958, and BG996), as well as verapamil and promethazine, to reverse chloroquine resistance was assessed against 24 chloroquine-resistant and 10 chloroquine-susceptible strains of Plasmodium falciparum from different countries. The 9,10-dihydroethanoanthracene derivatives clearly increase chloroquine susceptibility only in chloroquine-resistant isolates.


Subject(s)
Anthracenes/pharmacology , Antimalarials/pharmacology , Bridged-Ring Compounds/pharmacology , Chloroquine/pharmacology , Plasmodium falciparum/drug effects , Animals , Drug Resistance , Humans , Malaria, Falciparum/parasitology , Structure-Activity Relationship
12.
Eur J Med Chem ; 38(3): 253-63, 2003 Mar.
Article in English | MEDLINE | ID: mdl-12667692

ABSTRACT

A set of 9,10-dihydro-9,10-ethano and ethenoanthracene derivatives was tested with the aim to quantify the effect observed on drug efflux. Structure activity relationships and molecular modeling studies allowed to define topological display of pharmacophoric groups for these reversal agents.


Subject(s)
Anthracenes/chemical synthesis , Anthracenes/pharmacology , Drug Resistance, Multiple/physiology , Drug Resistance, Neoplasm/physiology , Pharmaceutical Preparations/metabolism , Animals , Cell Line, Tumor , Chromatography, Thin Layer , Computational Biology , Fluorescent Dyes , Hydrogen Bonding , Indicators and Reagents , Mice , Models, Molecular , Propafenone/chemistry , Quantitative Structure-Activity Relationship , Rhodamine 123
13.
J Med Chem ; 45(15): 3195-209, 2002 Jul 18.
Article in English | MEDLINE | ID: mdl-12109904

ABSTRACT

To suggest a mechanism of action for drugs capable to reverse the chloroquine resistance, a new set of 9,10-dihydro-9,10-ethano and ethenoanthracene derivatives was synthesized and compounds were tested with the aim to assess their effect on chloroquine susceptibility in Plasmodium falciparum resistant strains. With respect to this, reversal of resistance and change in drug accumulation were compared. Structure-activity relationship and molecular modeling studies made it possible to define a pharmacophoric moiety for reversal agents and to propose a putative model of interaction with some selected amino acids.


Subject(s)
Anthracenes/chemical synthesis , Antimalarials/chemical synthesis , Chloroquine/pharmacology , Plasmodium falciparum/drug effects , Animals , Anthracenes/chemistry , Anthracenes/pharmacology , Antimalarials/chemistry , Antimalarials/pharmacology , CHO Cells , Chloroquine/metabolism , Cricetinae , Drug Resistance, Multiple , Erythrocytes/drug effects , Erythrocytes/parasitology , In Vitro Techniques , Models, Molecular , Structure-Activity Relationship
14.
Antimicrob Agents Chemother ; 46(7): 2061-8, 2002 Jul.
Article in English | MEDLINE | ID: mdl-12069956

ABSTRACT

The effects of a series of dihydroethano- and ethenoanthracene derivatives on chloroquine (CQ) accumulation in CQ-susceptible strain 3D7 and CQ-resistant clone W2 were assessed. The levels of CQ accumulation increased little or none in CQ-susceptible strain 3D7 and generally increased markedly in CQ-resistant strain W2. At 10 microM, 28 compounds yielded cellular accumulation ratios (CARs) greater than that observed with CQ alone in W2. At 10 microM, in strain W2, 21 of 31 compounds had CQ CARs two or more times higher than that of CQ alone, 15 of 31 compounds had CQ CARs three or more times higher than that of CQ alone, 13 of 31 compounds had CQ CARs four or more times higher than that of CQ alone, and 9 of 31 compounds had CQ CARs five or more times higher than that of CQ alone. At 1 microM, 17 of 31 compounds had CQ CARs two or more times higher than that of CQ alone, 12 of 31 compounds had CQ CARs three or more times higher than that of CQ alone, 6 of 31 compounds had CQ CARs four or more times higher than that of CQ alone, and 3 of 31 compounds had CQ CARs five or more times higher than that of CQ alone. At 1 microM, 17 of 31 compounds were more potent inducers of CQ accumulation than verapamil and 12 of 31 compounds were more potent inducers of CQ accumulation than promethazine. The nature of the basic group seems to be associated with increases in the levels of CQ accumulation. At 1 and 10 microM, 10 of 14 and 13 of 14 compounds with amino group (amines and diamines), respectively, had CARs >or=3, while at 1 and 10 microM, only 1 of the 13 derivatives with amido groups had CARs >or=3. Among 12 of the 31 compounds which were more active inducers of CQ accumulation than promethazine at 1 microM, 10 had amino groups and 1 had an amido group.


Subject(s)
Anthracenes/pharmacology , Antimalarials/metabolism , Chloroquine/metabolism , Erythrocytes/parasitology , Plasmodium falciparum/drug effects , Animals , Chloroquine/pharmacology , Drug Resistance , Drug Synergism , Erythrocytes/metabolism , Structure-Activity Relationship
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