RESUMEN
Compared to normal cells, tumour cells exhibit an upregulation of glucose transporters and an increased rate of glycolytic activity. In previous research, we successfully identified a promising hit compound BH10 through a rigorous screening process, which demonstrates a potent capacity for inhibiting cancer cell proliferation by targeting glucose metabolism. In the current study, we identify Kelch-like ECH-associated protein 1 (Keap1) as a potential protein target of BH10via avidin pull-down assays with biotinylated-BH10. Subsequently, we present a comprehensive analysis of a series of BH10 analogues characterized by the incorporation of a naphthoimidazole scaffold and the introduction of a triazole ring with diverse terminal functional groups. Notably, compound 4d has emerged as the most potent candidate, exhibiting better anti-cancer activities against HEC1A cancer cells with an IC50 of 2.60 µM, an extended biological half-life, and an improved pharmacokinetic profile (compared to BH10) in mice.
Asunto(s)
Antineoplásicos , Proliferación Celular , Relación Dosis-Respuesta a Droga , Diseño de Fármacos , Ensayos de Selección de Medicamentos Antitumorales , Glucosa , Antineoplásicos/farmacología , Antineoplásicos/síntesis química , Antineoplásicos/química , Humanos , Proliferación Celular/efectos de los fármacos , Animales , Glucosa/metabolismo , Glucosa/antagonistas & inhibidores , Relación Estructura-Actividad , Estructura Molecular , Ratones , Línea Celular TumoralRESUMEN
It is well established that the quorum sensing (QS) in Pseudomonas aeruginosa is primarily responsible for the synthesis and the release of several virulence factors including pyocyanin and are involved in biofilm formation. In the Pseudomonas quinolone signal (PQS) system, autoinducers such as PQS and HHQ bind and activate the transcription regulator protein receptor PqsR (MvfR). Targeting PqsR with competitive inhibitors could be a promising strategy to inhibit QS in P. aeruginosa to overcome antimicrobial resistance. In this study, we have designed and synthesized a series of novel quinazolinone disulfide-containing competitive inhibitor of PqsR. The most potent analogue 8q efficiently inhibited the pqs system with an IC50 value of 4.5 µM. It also showed complete suppression of pyocyanin production and a significant reduction in biofilm formation by P. aeruginosa (PAO1) with low cytotoxicity. Additionally, 8q produced synergy in combination with known antibiotics such as ciprofloxacin and tobramycin. Finally, molecular docking analysis suggested that compound 8q could bind with the ligand-binding domain of PqsR in a similar fashion to the native ligand.
Asunto(s)
Pseudomonas aeruginosa , Percepción de Quorum , Pseudomonas aeruginosa/fisiología , Piocianina , Ligandos , Simulación del Acoplamiento Molecular , Quinazolinonas/farmacología , Quinazolinonas/metabolismo , Disulfuros/farmacología , Biopelículas , Proteínas Bacterianas/metabolismoRESUMEN
Bacteria readily acquire resistance to traditional antibiotics, resulting in pan-resistant strains with no available treatment. Antimicrobial resistance is a global challenge and without the development of effective antimicrobials, the foundation of modern medicine is at risk. Combination therapies such as antibiotic-antibiotic and antibiotic-adjuvant combinations are strategies used to combat antibiotic resistance. Current research focuses on antimicrobial peptidomimetics as adjuvant compounds, due to their promising activity against antibiotic-resistant bacteria. Here, for the first time we demonstrate that antibiotic-peptidomimetic combinations mitigate the development of antibiotic resistance in Staphylococcus aureus and Pseudomonas aeruginosa. When ciprofloxacin and gentamicin were passaged individually at sub-inhibitory concentrations for 10 days, the minimum inhibitory concentrations (MICs) increased up to 32-fold and 128-fold for S. aureus and P. aeruginosa, respectively. In contrast, when antibiotics were passaged in combination with peptidomimetics (Melimine, Mel4, RK758), the MICs of both antibiotics and peptidomimetics remained constant, indicating these combinations were able to mitigate the development of antibiotic-resistance. Furthermore, antibiotic-peptidomimetic combinations demonstrated synergistic activity against both Gram-positive and Gram-negative bacteria, reducing the concentration needed for bactericidal activity. This has significant potential clinical applications-including preventing the spread of antibiotic-resistant strains in hospitals and communities, reviving ineffective antibiotics, and lowering the toxicity of antimicrobial chemotherapy.
Asunto(s)
Antiinfecciosos , Peptidomiméticos , Antibacterianos/farmacología , Ciprofloxacina/farmacología , Peptidomiméticos/farmacología , Gentamicinas/farmacología , Staphylococcus aureus , Staphylococcus , Bacterias Gramnegativas , Bacterias Grampositivas , Antiinfecciosos/farmacología , Pseudomonas aeruginosa , Bacterias , Pruebas de Sensibilidad MicrobianaRESUMEN
A synthetic pathway to a novel 4-aryl-3,4-dihydro-2H-1,4-benzoxazine scaffold was developed and a series of compounds based on the scaffold were synthesised as potential anticancer agents. The 4-aryl-substituted compounds were prepared via Buchwald-Hartwig cross-coupling between substituted bromobenzenes and various 1,4-benzoxazines, which in turn were generated from a cascade hydrogenation and reductive amination one-pot reaction. These analogues exhibited moderate to good potency against various cancer cell lines. Structure-activity relationship analysis indicated that the inclusion of hydroxyl groups on ring A and ring B was beneficial to biological activity, while having a para-amino group on ring C significantly enhanced potency. Molecule 14f displayed the most potent anticancer activity (IC50 = 7.84-16.2 µM against PC-3, NHDF, MDA-MB-231, MIA PaCa-2, and U-87 MG cancer cell lines), indicating its potential as a lead compound for further structural optimisation. All the synthesised compounds were fully characterised with NMR, HMRS, and IR. The novel benzoxazine scaffold described in this study holds promise and deserves further in-depth studies.
Asunto(s)
Benzoxazinas , Bromobencenos , Benzoxazinas/farmacología , Hidrogenación , Aminación , Línea CelularRESUMEN
A series of hybrid compounds that incorporated anthranilic acid with activated 1H-indoles through a glyoxylamide linker were designed to target bacterial RNA polymerase holoenzyme formation using computational docking. Synthesis, in vitro transcription inhibition assays, and biological testing of the hybrids identified a range of potent anti-transcription inhibitors with activity against a range of pathogenic bacteria with MICs as low as 3.1 µM. A structure activity relationship study identified the key structural components necessary for inhibition of both bacterial growth and transcription. Correlation of in vitro transcription inhibition activity with in vivo mechanism of action was established using fluorescence microscopy and resistance passaging using Gram-positive bacteria showed no resistance development over 30 days. Furthermore, no toxicity was observed from the compounds in a wax moth larvae model, establishing a platform for the development of a series of new antibacterial drugs with an established mode of action.
Asunto(s)
Antibacterianos/farmacología , ARN Polimerasas Dirigidas por ADN/antagonistas & inhibidores , Inhibidores Enzimáticos/farmacología , Bacterias Grampositivas/efectos de los fármacos , Animales , Antibacterianos/síntesis química , Antibacterianos/química , ARN Polimerasas Dirigidas por ADN/metabolismo , Relación Dosis-Respuesta a Droga , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/química , Bacterias Grampositivas/enzimología , Pruebas de Sensibilidad Microbiana , Estructura Molecular , Mariposas Nocturnas , Relación Estructura-ActividadRESUMEN
The prevention and treatment of biofilm-mediated infections remains an unmet clinical need for medical devices. With the increasing prevalence of antibiotic-resistant infections, it is important that novel approaches are developed to prevent biofilms forming on implantable medical devices. This study presents a versatile and simple polydopamine surface coating technique for medical devices, using a new class of antibiotics-antimicrobial peptidomimetics. Their unique mechanism of action primes them for activity against antibiotic-resistant bacteria and makes them suitable for covalent attachment to medical devices. This study assesses the anti-biofilm activity of peptidomimetics, characterises the surface chemistry of peptidomimetic coatings, quantifies the antibacterial activity of coated surfaces and assesses the biocompatibility of these coated materials. X-ray photoelectron spectroscopy and water contact angle measurements were used to confirm the chemical modification of coated surfaces. The antibacterial activity of surfaces was quantified for S. aureus, E. coli and P. aeruginosa, with all peptidomimetic coatings showing the complete eradication of S. aureus on surfaces and variable activity for Gram-negative bacteria. Scanning electron microscopy confirmed the membrane disruption mechanism of peptidomimetic coatings against E. coli. Furthermore, peptidomimetic surfaces did not lyse red blood cells, which suggests these surfaces may be biocompatible with biological fluids such as blood. Overall, this study provides a simple and effective antibacterial coating strategy that can be applied to biomaterials to reduce biofilm-mediated infections.
Asunto(s)
Antiinfecciosos , Peptidomiméticos , Antibacterianos/química , Antibacterianos/farmacología , Antiinfecciosos/farmacología , Biopelículas , Materiales Biocompatibles Revestidos/química , Materiales Biocompatibles Revestidos/farmacología , Escherichia coli , Indoles , Peptidomiméticos/farmacología , Polímeros , Pseudomonas aeruginosa , Staphylococcus aureusRESUMEN
There is a significant and urgent need for the development of novel antibacterial agents to tackle the increasing incidence of antibiotic resistance. Cholic acid-based small molecular antimicrobial peptide mimics are reported as potential new leads to treat bacterial infection. Here, we describe the design, synthesis and biological evaluation of cholic acid-based small molecular antimicrobial peptide mimics. The synthesis of cholic acid analogues involves the attachment of a hydrophobic moiety at the carboxyl terminal of the cholic acid scaffold, followed by the installation of one to three amino acid residues on the hydroxyl groups present on the cholic acid scaffold. Structure-activity relationship studies suggest that the tryptophan moiety is important for high antibacterial activity. Moreover, a minimum of +2 charge is also important for antimicrobial activity. In particular, analogues containing lysine-like residues showed the highest antibacterial potency against Gram-positive S. aureus. All di-substituted analogues possess high antimicrobial activity against both Gram-positive S. aureus as well as Gram-negative E. coli and P. aeruginosa. Analogues 17c and 17d with a combination of these features were found to be the most potent in this study. These compounds were able to depolarise the bacterial membrane, suggesting that they are potential antimicrobial pore forming agents.
Asunto(s)
Antibacterianos , Antiinfecciosos , Antibacterianos/química , Antiinfecciosos/farmacología , Péptidos Antimicrobianos , Ácido Cólico/farmacología , Escherichia coli , Pruebas de Sensibilidad Microbiana , Staphylococcus aureus , Relación Estructura-ActividadRESUMEN
The Pseudomonas quinolone system (pqs) is one of the key quorum sensing systems in antibiotic-resistant P. aeruginosa and is responsible for the production of virulence factors and biofilm formation. Thus, synthetic small molecules that can target the PqsR (MvfR) receptor can be utilized as quorum sensing inhibitors to treat P. aeruginosa infections. In this study, we report the synthesis of novel thioether-linked dihydropyrrol-2-one (DHP) analogues as PqsR antagonists. Compound 7g containing a 2-mercaptopyridyl linkage effectively inhibited the pqs system with an IC50 of 32 µM in P. aeruginosa PAO1. Additionally, these inhibitors significantly reduced bacterial aggregation and biofilm formation without affecting planktonic growth. The molecular docking study suggest that these inhibitors bind with the ligand binding domain of the MvfR as a competitive antagonist.
Asunto(s)
Antibacterianos/farmacología , Farmacorresistencia Bacteriana/efectos de los fármacos , Pseudomonas aeruginosa/efectos de los fármacos , Pirroles/farmacología , Sulfuros/farmacología , Antibacterianos/síntesis química , Antibacterianos/química , Relación Dosis-Respuesta a Droga , Pruebas de Sensibilidad Microbiana , Estructura Molecular , Pirroles/química , Percepción de Quorum/efectos de los fármacos , Relación Estructura-Actividad , Sulfuros/químicaRESUMEN
The rapid emergence of drug-resistant bacteria is a major global health concern. Antimicrobial peptides (AMPs) and peptidomimetics have arisen as a new class of antibacterial agents in recent years in an attempt to overcome antibiotic resistance. A library of phenylglyoxamide-based small molecular peptidomimetics was synthesised by incorporating an N-alkylsulfonyl hydrophobic group with varying alkyl chain lengths and a hydrophilic cationic group into a glyoxamide core appended to phenyl ring systems. The quaternary ammonium iodide salts 16d and 17c showed excellent minimum inhibitory concentration (MIC) of 4 and 8 µM (2.9 and 5.6 µg/mL) against Staphylococcus aureus, respectively, while the guanidinium hydrochloride salt 34a showed an MIC of 16 µM (8.5 µg/mL) against Escherichia coli. Additionally, the quaternary ammonium iodide salt 17c inhibited 70% S. aureus biofilm formation at 16 µM. It also disrupted 44% of pre-established S. aureus biofilms at 32 µM and 28% of pre-established E. coli biofilms 64 µM, respectively. A cytoplasmic membrane permeability study indicated that the synthesised peptidomimetics acted via disruption and depolarisation of membranes. Moreover, the quaternary ammonium iodide salts 16d and 17c were non-toxic against human cells at their therapeutic dosages against S. aureus.
Asunto(s)
Antibacterianos , Biopelículas/efectos de los fármacos , Escherichia coli/fisiología , Peptidomiméticos , Staphylococcus aureus/fisiología , Antibacterianos/síntesis química , Antibacterianos/química , Antibacterianos/farmacología , Biopelículas/crecimiento & desarrollo , Peptidomiméticos/síntesis química , Peptidomiméticos/química , Peptidomiméticos/farmacología , Relación Estructura-Actividad , Compuestos de Sulfonilurea/síntesis química , Compuestos de Sulfonilurea/química , Compuestos de Sulfonilurea/farmacologíaRESUMEN
Rottlerin is a natural product consisting of chalcone and flavonoid scaffolds, both of which have previously shown quorum sensing (QS) inhibition in various bacteria. Therefore, the unique rottlerin scaffold highlights great potential in inhibiting the QS system of Pseudomonas aeruginosa. Rottlerin analogues were synthesised by modifications at its chalcone- and methylene-bridged acetophenone moieties. The synthesis of analogues was achieved using an established five-step synthetic strategy for chalcone derivatives and utilising the Mannich reaction at C6 of the chromene to construct morpholine analogues. Several pyranochromene chalcone derivatives were also generated using aldol conditions. All the synthetic rottlerin derivatives were screened for QS inhibition and growth inhibition against the related LasR QS system. The pyranochromene chalcone structures displayed high QS inhibitory activity with the most potent compounds, 8b and 8d, achieving QS inhibition of 49.4% and 40.6% and no effect on bacterial growth inhibition at 31 µM, respectively. Both compounds also displayed moderate biofilm inhibitory activity and reduced the production of pyocyanin.
Asunto(s)
Acetofenonas/farmacología , Benzopiranos/farmacología , Productos Biológicos/farmacología , Percepción de Quorum/efectos de los fármacos , Antibacterianos/farmacología , Biopelículas/efectos de los fármacos , Flavonoides/farmacología , Pruebas de Sensibilidad Microbiana/métodos , Pseudomonas aeruginosa/efectos de los fármacos , Piocianina/farmacologíaRESUMEN
The dihydropyranoindole structures were previously identified as promising scaffolds for improving the anti-cancer activity of histone deacetylase inhibitors. This work describes the synthesis of related furoindoles and their ability to synergize with suberoylanilide hydroxamic acid (SAHA) against neuroblastoma and breast cancer cells. The nucleophilic substitution of hydroxyindole methyl esters with α-haloketones yielded the corresponding arylether ketones, which were subsequently cyclized to tricyclic and tetracyclic furoindoles. The furoindoles showed promising individual cytotoxic efficiency against breast cancer cells, as well as decent SAHA enhancement against cancer cells in select cases. Interestingly, the best IC50 value was obtained with the non-cyclized intermediate.
Asunto(s)
Neoplasias de la Mama/enzimología , Inhibidores de Histona Desacetilasas/farmacología , Cetonas/síntesis química , Neuroblastoma/enzimología , Vorinostat/farmacología , Neoplasias de la Mama/tratamiento farmacológico , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Sinergismo Farmacológico , Femenino , Compuestos Heterocíclicos/síntesis química , Compuestos Heterocíclicos/química , Compuestos Heterocíclicos/farmacología , Humanos , Cetonas/química , Cetonas/farmacología , Células MCF-7 , Neuroblastoma/tratamiento farmacológicoRESUMEN
There has been an increasing interest in the development of antimicrobial peptides (AMPs) and their synthetic mimics as a novel class of antibiotics to overcome the rapid emergence of antibiotic resistance. Recently, phenylglyoxamide-based small molecular AMP mimics have been identified as potential leads to treat bacterial infections. In this study, a new series of biphenylglyoxamide-based small molecular AMP mimics were synthesised from the ring-opening reaction of N-sulfonylisatin bearing a biphenyl backbone with a diamine, followed by the conversion into tertiary ammonium chloride, quaternary ammonium iodide and guanidinium hydrochloride salts. Structure-activity relationship studies of the analogues identified the octanesulfonyl group as being essential for both Gram-positive and Gram-negative antibacterial activity, while the biphenyl backbone was important for Gram-negative antibacterial activity. The most potent analogue was identified to be chloro-substituted quaternary ammonium iodide salt 15c, which possesses antibacterial activity against both Gram-positive (MIC against Staphylococcus aureus = 8 µM) and Gram-negative bacteria (MIC against Escherichia coli = 16 µM, Pseudomonas aeruginosa = 63 µM) and disrupted 35% of pre-established S. aureus biofilms at 32 µM. Cytoplasmic membrane permeability and tethered bilayer lipid membranes (tBLMs) studies suggested that 15c acts as a bacterial membrane disruptor. In addition, in vitro toxicity studies showed that the potent compounds are non-toxic against human cells at therapeutic dosages.
Asunto(s)
Antibacterianos/síntesis química , Péptidos Catiónicos Antimicrobianos/síntesis química , Peptidomiméticos/síntesis química , Antibacterianos/farmacología , Antibacterianos/toxicidad , Péptidos Catiónicos Antimicrobianos/farmacología , Péptidos Catiónicos Antimicrobianos/toxicidad , Biopelículas/efectos de los fármacos , Compuestos de Bifenilo/química , Línea Celular , Diseño de Fármacos , Escherichia coli/efectos de los fármacos , Fibroblastos/efectos de los fármacos , Humanos , Membrana Dobles de Lípidos , Potenciales de la Membrana/efectos de los fármacos , Pruebas de Sensibilidad Microbiana , Estructura Molecular , Peptidomiméticos/farmacología , Peptidomiméticos/toxicidad , Staphylococcus aureus/efectos de los fármacos , Relación Estructura-Actividad , Compuestos de Sulfonilurea/químicaRESUMEN
The Pseudomonas quinolone system (PQS) is one of the three major interconnected quorum sensing signaling systems in Pseudomonas aeruginosa. The virulence factors PQS and HHQ activate the transcription regulator PqsR (MvfR), which controls several activities in bacteria, including biofilm formation and upregulation of PQS biosynthesis. The enzyme anthraniloyl-CoA synthetase (PqsA) catalyzes the first and critical step in the biosynthesis of quinolones; therefore, it is an attractive target for the development of anti-virulence therapeutics against Pseudomonas resistance. Herein, we report the design and synthesis of novel triazole nucleoside-based anthraniloyl- adenosine monophosphate (AMP) mimics. These analogues had a major impact on the morphology of bacterial biofilms and caused significant reduction in bacterial aggregation and population density. However, the compounds showed only limited inhibition of PQS and did not exhibit any effect on pyocyanin production.
Asunto(s)
Adenosina Monofosfato , Materiales Biomiméticos/farmacología , Pseudomonas aeruginosa , Quinolonas/metabolismo , Factores de Virulencia/biosíntesis , Adenosina Monofosfato/análogos & derivados , Adenosina Monofosfato/farmacología , Proteínas Bacterianas/metabolismo , Pseudomonas aeruginosa/crecimiento & desarrollo , Pseudomonas aeruginosa/patogenicidad , Factores de Transcripción/metabolismoRESUMEN
The dihydropyranoindole scaffold was identified as a promising target for improving the anti-cancer activity of HDAC inhibitors from the preliminary screening of a library of compounds. A suitable methodology has been developed for the preparation of novel dihydropyranoindoles via the Hemetsberger indole synthesis using azido-phenylacrylates, derived from the reaction of corresponding alkynyl-benzaldehydes with methyl azidoacetate, followed by thermal cyclization in high boiling solvents. Anti-cancer activity of all the newly synthesized compounds was evaluated against the SH-SY5Y and Kelly neuroblastoma cells as well as the MDA-MB-231 and MCF-7 breast adenocarcinoma cell lines. Biological studies showed that the tetracyclic systems had significant cytotoxic activity at higher concentration against the neuroblastoma cancer cells. More importantly, these systems, at the lower concentration, considerably enhanced the SAHA toxicity. In addition to that, the toxicity of designated systems on the healthy human cells was found to be significantly less than the cancer cells.
Asunto(s)
Antineoplásicos , Diseño de Fármacos , Inhibidores de Histona Desacetilasas , Neoplasias/tratamiento farmacológico , Antineoplásicos/síntesis química , Antineoplásicos/química , Antineoplásicos/farmacología , Proliferación Celular/efectos de los fármacos , Inhibidores de Histona Desacetilasas/síntesis química , Inhibidores de Histona Desacetilasas/química , Inhibidores de Histona Desacetilasas/farmacología , Humanos , Células MCF-7 , Estructura Molecular , Neoplasias/enzimología , Neoplasias/patología , Relación Estructura-ActividadRESUMEN
Bacteria regulate their pathogenicity and biofilm formation through quorum sensing (QS), which is an intercellular communication system mediated by the binding of signaling molecules to QS receptors such as LasR. In this study, a range of dihydropyrrolone (DHP) analogues were synthesized via the lactone-lactam conversion of lactone intermediates. The synthesized compounds were tested for their ability to inhibit QS, biofilm formation and bacterial growth of Pseudomonas aeruginosa. The compounds were also docked into a LasR crystal structure to rationalize the observed structure-activity relationships. The most active compound identified in this study was compound 9i, which showed 63.1% QS inhibition of at 31.25⯵M and 60% biofilm reduction at 250⯵M with only moderate toxicity towards bacterial cell growth.
Asunto(s)
Pseudomonas aeruginosa/efectos de los fármacos , Pirroles/farmacología , Proteínas Bacterianas , Biopelículas/efectos de los fármacos , Dominio Catalítico , Descubrimiento de Drogas , Modelos Moleculares , Conformación Proteica , Pseudomonas aeruginosa/fisiología , Pirroles/síntesis química , Pirroles/química , Percepción de Quorum/efectos de los fármacos , Relación Estructura-ActividadRESUMEN
Rottlerin (1) is a potent protein kinase C δ inhibitor that possesses a wide range of biological activities. However, the potential of this molecule to be developed as a drug has been restricted by its limited availability. We report herein a gram scale quantity synthesis of rottlerin in a five-step synthetic route that can be completed within 2 days. The methodology was extended by the reaction of the key aminochromene intermediate (15) with various electron-rich arenes, forming novel unsymmetrical methylene-bridged compounds. The X-ray crystal structure revealed the boomerang shape of this kind of molecule for the first time. The direct transformation of rottlerin (1) into the natural product, isorottlerin (35), was observed for the first time, and we named this transformation the "isorottlerin change". In addition, the antibacterial activities of rottlerin (1) and new rottlerin analogues 32-34 were examined against Staphylococcus aureus. The compounds showed MIC values as low as 2.0 µM, which were comparable to the clinically used antibiotic gentamicin.
Asunto(s)
Acetofenonas/síntesis química , Benzopiranos/síntesis química , Acetofenonas/química , Acetofenonas/farmacología , Antibacterianos/farmacología , Benzopiranos/química , Benzopiranos/farmacología , Pruebas de Sensibilidad Microbiana , Staphylococcus aureus/efectos de los fármacosRESUMEN
The bis-glyoxylamide peptidomimetics have been synthesized from bis-N-acetylisatins linked at C5 by ring-opening with alcohols, amines, and amino acid methyl ester hydrochlorides. X-ray images of single crystals of bis-glyoxylamide peptidomimetics have been obtained.
Asunto(s)
Indoles/síntesis química , Peptidomiméticos/síntesis química , Alcoholes/química , Aminas/química , Aminoácidos/química , Ésteres/química , Indoles/química , Isatina/química , Metano/análogos & derivados , Metano/química , Modelos Moleculares , Estructura Molecular , Oxígeno/química , Peptidomiméticos/química , Rayos XRESUMEN
We describe a library of amphiphilic anthranilamide compounds as antimicrobial peptide (AMP) mimics. These contain a hydrophobic naphthoyl side chain and different hydrophilic cationic groups such as amino, quaternary ammonium and guanidino groups. These are prepared via the ring-opening of different isatoic anhydrides. The antibacterial activity against S. aureus and E. coli of compounds containing guanidino cationic groups was greater than that for amino and quaternary ammonium cationic groups. The fluoro-substituted guanidinium compound 9b showed a minimum inhibitory concentration (MIC) of 2.0 µM against S. aureus, and reduced established biofilms of S. aureus by 92% at 64 µM concentration. The bromo-substituted guanidinium compound 9d exhibited good MIC against S. aureus (3.9 µM) and E. coli (15.6 µM) and disrupted established biofilms of S. aureus by 83% at 62.4 µM concentration. Cytoplasmic membrane permeability studies suggested that depolarization and disruption of the bacterial cell membrane could be a possible mechanism for antibacterial activity and the in vitro toxicity studies against MRC-5 human lung fibroblast cells showed that the potent compounds are non-toxic against mammalian cells.
RESUMEN
Bacterial infections, particularly hospital-acquired infections caused by Pseudomonas aeruginosa, have become a global threat with a high mortality rate. Gram-negative bacteria including P. aeruginosa employ N-acyl homoserine lactones (AHLs) as chemical signals to regulate the expression of pathogenic phenotypes through a mechanism called quorum sensing (QS). Recently, strategies targeting bacterial behaviour or QS have received great attention due to their ability to disarm rather than kill pathogenic bacteria, which lowers the evolutionary burden on bacteria and the risk of resistance development. In the present study, we report the design and synthesis of N-alkyl- and N-aryl 3,4 dichloro- and 3,4-dibromopyrrole-2-one derivatives through the reductive amination of mucochloric and mucobromic acid with aliphatic and aromatic amines. The quorum sensing inhibition (QSI) activity of the synthesized compounds was determined against a P. aeruginosa MH602 reporter strain. The phenolic compounds exhibited the best activity with 80% and 75% QSI at 250 µM and were comparable in activity to the positive control compound Fu-30. Computational docking studies performed using the LasR receptor protein of P. aeruginosa suggested the importance of hydrogen bonding and hydrophobic interactions for QSI.