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1.
Molecules ; 26(16)2021 Aug 19.
Artigo em Inglês | MEDLINE | ID: mdl-34443612

RESUMO

Eucalyptus leaves (ELE) and willow bark (WBE) extracts were utilized towards the formation of silver nanoparticles (AgNPs(ELE), AgNPs(WBE)). AgNPs(ELE) and AgNPs(WBE) were dispersed in polymer hydrogels to create pHEMA@AgNPs(ELE)_2 and pHEMA@AgNPs(WBE)_2 using hydroxyethyl-methacrylate (HEMA). The materials were characterized in a solid state by X-ray fluorescence (XRF) spectroscopy, X-ray powder diffraction analysis (XRPD), thermogravimetric differential thermal analysis (TG-DTA), differential scanning calorimetry (DTG/DSC) and attenuated total reflection spectroscopy (ATR-FTIR) and ultraviolet visible (UV-vis) spectroscopy in solution. The antimicrobial potential of the materials was investigated against the Gram-negative bacterial strain Pseudomonas aeruginosa (P. aeruginosa) and the Gram-positive bacterial strain of the genus Staphylococcus epidermidis (S. epidermidis) and Staphylococcus aureus (S. aureus), which are involved in microbial keratitis. The percentage of bacterial viability of P. aeruginosa and S. epidermidis upon their incubation over the pHEMA@AgNPs(ELE)_2 discs is interestingly low (28.3 and 6.8% respectively), while the inhibition zones (IZ) formed are 12.3 ± 1.7 and 13.2 ± 1.2 mm, respectively. No in vitro toxicity of this material towards human corneal epithelial cells (HCEC) was detected. Despite its low performance against S. aureus, pHEMA@AgNPs(ELE)_2 could be an efficient candidate towards the development of contact lenses that reduces microbial infection risk.


Assuntos
Lentes de Contato/microbiologia , Eucalyptus/química , Hidrogéis/química , Extratos Vegetais/química , Salix/química , Prata/farmacologia , Antibacterianos/síntese química , Antibacterianos/química , Antibacterianos/farmacologia , Humanos , Nanopartículas Metálicas , Testes de Sensibilidade Microbiana , Prata/química
2.
Molecules ; 26(12)2021 Jun 10.
Artigo em Inglês | MEDLINE | ID: mdl-34200814

RESUMO

Multi-drug resistant pathogens are a rising danger for the future of mankind. Iodine (I2) is a centuries-old microbicide, but leads to skin discoloration, irritation, and uncontrolled iodine release. Plants rich in phytochemicals have a long history in basic health care. Aloe Vera Barbadensis Miller (AV) and Salvia officinalis L. (Sage) are effectively utilized against different ailments. Previously, we investigated the antimicrobial activities of smart triiodides and iodinated AV hybrids. In this work, we combined iodine with Sage extracts and pure AV gel with polyvinylpyrrolidone (PVP) as an encapsulating and stabilizing agent. Fourier transform infrared spectroscopy (FT-IR), Ultraviolet-visible spectroscopy (UV-Vis), Surface-Enhanced Raman Spectroscopy (SERS), microstructural analysis by scanning electron microscopy (SEM), energy dispersive spectroscopy (EDS), and X-Ray-Diffraction (XRD) analysis verified the composition of AV-PVP-Sage-I2. Antimicrobial properties were investigated by disc diffusion method against 10 reference microbial strains in comparison to gentamicin and nystatin. We impregnated surgical sutures with our biohybrid and tested their inhibitory effects. AV-PVP-Sage-I2 showed excellent to intermediate antimicrobial activity in discs and sutures. The iodine within the polymeric biomaterial AV-PVP-Sage-I2 and the synergistic action of the two plant extracts enhanced the microbial inhibition. Our compound has potential for use as an antifungal agent, disinfectant and coating material on sutures to prevent surgical site infections.


Assuntos
Antibacterianos/química , Antibacterianos/síntese química , Aloe/química , Antifúngicos/química , Gentamicinas/química , Testes de Sensibilidade Microbiana , Microscopia Eletrônica de Varredura/métodos , Nistatina/química , Extratos Vegetais/química , Povidona/química , Salvia/química , Salvia officinalis/química , Espectrometria por Raios X/métodos , Espectroscopia de Infravermelho com Transformada de Fourier/métodos , Difração de Raios X/métodos
3.
Bioorg Chem ; 114: 105153, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34328851

RESUMO

A series of novel substituted phenyl 1, 3-thiazolidin-4-one sulfonyl derivatives 5 (a-t) were synthesized and screened for their in-vitro anti-microbial and anti-viral activity. The result of the anti-microbial assay demonstrated compounds 5d, 5f, 5g, 5h, 5i, 5j showed prominent inhibitory activity against all the tested Gram-positive and Gram-negative bacterial strains, while compounds 5g, 5j, 5o, 5p, 5q showed significant activity against the entire set of fungal strains as compared to standard drug Ampicillin and Clotrimazole, respectively. The antimicrobial study revealed that compounds having electron-withdrawing groups showed significant antimicrobial potency. The most active antibacterial compound 5j showed potent inhibition of S. aureus DNA Gyrase enzyme as a possible mechanism of action for antimicrobial activity. Moreover, the antiviral testing of selected compounds showed considerable activity against Herpes simplex virus-1(KOS), Herpes simplex virus-2 (G), Herpes simplex virus-1(TK- KOS ACVr), Vaccinia virus, Human Coronavirus (229E), Reovirus-1, Sindbis virus, Coxsackie virus B4, Yellow Fever virus and Influenza A, B virus. Compounds 5h exhibited low anti-viral activity against HIV-1(strain IIIB) and HIV-2 (strain ROD). The study clearly outlined that synthesized compounds endowed with good antimicrobial property together with considerable antiviral activity.


Assuntos
Fenóis/síntese química , Sulfonamidas/síntese química , Tolueno/análogos & derivados , Animais , Antibacterianos/síntese química , Antibacterianos/química , Antibacterianos/farmacologia , Antivirais/síntese química , Antivirais/química , Antivirais/farmacologia , Bactérias/classificação , Bactérias/efeitos dos fármacos , Linhagem Celular , Chlorocebus aethiops , Humanos , Fenóis/química , Fenóis/farmacologia , Sulfonamidas/química , Sulfonamidas/farmacologia , Tolueno/síntese química , Tolueno/química , Tolueno/farmacologia , Células Vero , Vírus/classificação , Vírus/efeitos dos fármacos
4.
J Enzyme Inhib Med Chem ; 36(1): 1509-1520, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-34238110

RESUMO

In the present study, a series of azo derivatives (TR-1 to TR-9) have been synthesised via the diazo-coupling approach between substituted aromatic amines with phenol or naphthol derivatives. The compounds were evaluated for their therapeutic applications against alpha-glucosidase (anti-diabetic) and pathogenic bacterial strains E. coli (gram-negative), S. aureus (gram-positive), S. aureus (gram-positive) drug-resistant strain, P. aeruginosa (gram-negative), P. aeruginosa (gram-negative) drug-resistant strain and P. vulgaris (gram-negative). The IC50 (µg/mL) of TR-1 was found to be most effective (15.70 ± 1.3 µg/mL) compared to the reference drug acarbose (21.59 ± 1.5 µg/mL), hence, it was further selected for the kinetic studies in order to illustrate the mechanism of inhibition. The enzyme inhibitory kinetics and mode of binding for the most active inhibitor (TR-1) was performed which showed that the compound is a non-competitive inhibitor and effectively inhibits the target enzyme by binding to its binuclear active site reversibly.


Assuntos
Antibacterianos/farmacologia , Compostos Azo/farmacologia , Inibidores Enzimáticos/farmacologia , Hipoglicemiantes/farmacologia , Simulação de Acoplamento Molecular , alfa-Glucosidases/metabolismo , Antibacterianos/síntese química , Antibacterianos/química , Compostos Azo/síntese química , Compostos Azo/química , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Escherichia coli/efeitos dos fármacos , Hipoglicemiantes/síntese química , Hipoglicemiantes/química , Cinética , Testes de Sensibilidade Microbiana , Estrutura Molecular , Pseudomonas aeruginosa/efeitos dos fármacos , Saccharomyces cerevisiae/enzimologia , Staphylococcus aureus/efeitos dos fármacos
5.
AAPS PharmSciTech ; 22(6): 205, 2021 Jul 20.
Artigo em Inglês | MEDLINE | ID: mdl-34286391

RESUMO

Drug-loaded electrospun fibers have attracted increasing attention as a promising wound dressing material due to their capability of preventing from infections and inflammation and maintaining an appropriate environment for wound healing. In this study, polylactic acid (PLA), which is widely used in wound management, was chosen as electrospinnable polymer. A triterpene extract (TE) from the outer bark of birch known for its anti-inflammatory, antiviral, antibacterial, and wound healing effects was chosen to produce TE-loaded PLA electrospun fibers for wound dressing. A binary solvent system of dichloromethane (DCM) and dimethyl sulfoxide (DMSO) was employed, and the ratio of the solvents was optimized for preparing smooth and uniform fibers. The morphology of TE-loaded PLA electrospun fibers was investigated by scanning electron microscopy (SEM). The entrapment of TE in PLA fibers was confirmed by confocal laser scanning microscopy (CLSM). Differential scanning calorimetry (DSC) and X-ray diffraction (XRD) were used to analyze the solid state of TE in PLA fibers. The release behavior of TE was assayed by a shaking flask method for a period of 96 h. The results revealed that TE-loaded electrospun PLA microfibers could be reliably prepared and are promising future candidates in wound therapy.


Assuntos
Bandagens , Betula/química , Nanofibras/química , Casca de Planta/química , Poliésteres/síntese química , Triterpenos/síntese química , Antibacterianos/análise , Antibacterianos/síntese química , Química Farmacêutica/métodos , Nanofibras/análise , Extratos Vegetais/análise , Extratos Vegetais/síntese química , Poliésteres/análise , Triterpenos/análise
6.
Molecules ; 26(14)2021 Jul 06.
Artigo em Inglês | MEDLINE | ID: mdl-34299385

RESUMO

An efficient and simple protocol for the synthesis of a new class of diverse bis(indolyl)pyridines analogues of the marine alkaloid nortopsentin has been reported. A one-pot four-component condensation of 3-cyanocarbomethylindole, various aldehyde, 3-acetylindole, and ammonium acetate in glacial acetic acid led to the formation of 2,6-bis(1H-indol-3-yl)-4-(substituted-phenyl)pyridine-5-carbonitriles. Additionally, 2,6-bis(1H-indol-3-yl)-4-(benzofuran) pyridine-5-carbonitriles were prepared via a one-pot four-component condensation of 3-cyanocarbomethylindole, various N-substituted-indole-3-aldehydes, 2-acetylbenzofuran, and ammonium acetate. The synthesized compounds were evaluated for their ability to inhibit biofilm formation against the Gram-positive bacterial reference strains Staphylococcus aureus ATCC 6538 and the Gram-negative strain Escherichia coli ATCC 25922. Some of the new compounds showed a marked selectivity against the Gram-positive and Gram-negative strains. Remarkably, five compounds 4b, 7a, 7c, 7d and 8e demonstrated good antibiofilm formation against S. aureus and E. coli. On the other hand, the release of reducing sugars and proteins from the treated bacterial strains over the untreated strains was considered to explain the disruption effect of the selected compound on the contact cells of S. aureus and E. coli. Out of all studied compounds, the binding energies and binding mode of bis-indole derivatives 7c and 7d were theoretically the best thymidylate kinase, DNA gyrase B and DNA topoisomerase IV subunit B inhibitors.


Assuntos
Alcaloides/química , Antibacterianos/síntese química , Antibacterianos/farmacologia , Bactérias/efeitos dos fármacos , Biofilmes/crescimento & desenvolvimento , Inibidores Enzimáticos/farmacologia , Indóis/química , Biofilmes/efeitos dos fármacos , DNA Girase/química , DNA Topoisomerase IV/antagonistas & inibidores , Inibidores Enzimáticos/química , Simulação de Acoplamento Molecular , Núcleosídeo-Fosfato Quinase/antagonistas & inibidores , Piridinas/química
7.
Int J Mol Sci ; 22(14)2021 Jul 08.
Artigo em Inglês | MEDLINE | ID: mdl-34298964

RESUMO

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.


Assuntos
Antibacterianos , Biofilmes/efeitos dos fármacos , Escherichia coli/fisiologia , Peptidomiméticos , Staphylococcus aureus/fisiologia , Antibacterianos/síntese química , Antibacterianos/química , Antibacterianos/farmacologia , Biofilmes/crescimento & desenvolvimento , Peptidomiméticos/síntese química , Peptidomiméticos/química , Peptidomiméticos/farmacologia , Relação Estrutura-Atividade , Compostos de Sulfonilureia/síntese química , Compostos de Sulfonilureia/química , Compostos de Sulfonilureia/farmacologia
8.
Int J Mol Sci ; 22(13)2021 Jun 30.
Artigo em Inglês | MEDLINE | ID: mdl-34208826

RESUMO

PEGylation of antimicrobial peptides as a shielding tool that increases stability toward proteolytic degradation typically leads to concomitant loss of activity, whereas incorporation of ultrashort PEG-like amino acids (sPEGs) remains essentially unexplored. Here, modification of a peptide/ß-peptoid hybrid with sPEGs was examined with respect to influence on hydrophobicity, antibacterial activity and effect on viability of mammalian cells for a set of 18 oligomers. Intriguingly, the degree of sPEG modification did not significantly affect hydrophobicity as measured by retention in reverse-phase HPLC. Antibacterial activity against both wild-type and drug-resistant strains of Escherichia coli and Acinetobacter baumannii (both Gram-negative pathogens) was retained or slightly improved (MICs in the range 2-16 µg/mL equal to 0.7-5.2 µM). All compounds in the series exhibited less than 10% hemolysis at 400 µg/mL. While the number of sPEG moieties appeared not to be clearly correlated with hemolytic activity, a trend toward slightly increased hemolytic activity was observed for analogues displaying the longest sPEGs. In contrast, within a subseries the viability of HepG2 liver cells was least affected by analogues displaying the longer sPEGs (with IC50 values of ~1280 µg/mL) as compared to most other analogues and the parent peptidomimetic (IC50 values in the range 330-800 µg/mL).


Assuntos
Antibacterianos/síntese química , Peptidomiméticos/síntese química , Peptoides/síntese química , Polietilenoglicóis/química , Acinetobacter baumannii/efeitos dos fármacos , Antibacterianos/química , Antibacterianos/farmacologia , Sobrevivência Celular/efeitos dos fármacos , Farmacorresistência Bacteriana/efeitos dos fármacos , Escherichia coli/efeitos dos fármacos , Hemólise , Células Hep G2 , Humanos , Interações Hidrofóbicas e Hidrofílicas , Testes de Sensibilidade Microbiana , Estrutura Molecular , Peptidomiméticos/química , Peptidomiméticos/farmacologia , Peptoides/química , Peptoides/farmacologia
9.
Molecules ; 26(13)2021 Jun 25.
Artigo em Inglês | MEDLINE | ID: mdl-34202191

RESUMO

Twenty-two novel, variously substituted nitroazetidines were designed as both sulfonamide and urethane vinylogs possibly endowed with antimicrobial activity. The compounds under study were obtained following a general procedure recently developed, starting from 4-nitropentadienoates deriving from a common ß-nitrothiophenic precursor. While being devoid of any activity against fungi and Gram-negative bacteria, most of the title compounds performed as potent antibacterial agents on Gram-positive bacteria (E. faecalis and three strains of S. aureus), with the most potent congener being the 1-(4-chlorobenzyl)-3-nitro-4-(p-tolyl)azetidine 22, which displayed potency close to that of norfloxacin, the reference antibiotic (minimum inhibitory concentration values 4 and 1-2 µg/mL, respectively). Since 22 combines a relatively efficient activity against Gram-positive bacteria and a cytotoxicity on eucharyotic cells only at 4-times higher concentrations (inhibiting concentration on 50% of the cultured eukaryotic cells: 36 ± 10 µM, MIC: 8.6 µM), it may be considered as a promising hit compound for the development of a new series of antibacterials selectively active on Gram-positive pathogens. The relatively concise synthetic route described herein, based on widely available starting materials, could feed further structure-activity relationship studies, thus allowing for the fine investigation and optimization of the toxico-pharmacological profile.


Assuntos
Antibacterianos , Azetidinas , Enterococcus faecalis/crescimento & desenvolvimento , Staphylococcus aureus/crescimento & desenvolvimento , Antibacterianos/síntese química , Antibacterianos/química , Antibacterianos/farmacologia , Azetidinas/síntese química , Azetidinas/química , Azetidinas/farmacologia , Relação Dose-Resposta a Droga , Avaliação de Medicamentos , Células Hep G2 , Humanos , Relação Estrutura-Atividade
10.
Molecules ; 26(13)2021 Jun 22.
Artigo em Inglês | MEDLINE | ID: mdl-34206375

RESUMO

This research aimed to enhance the antibacterial activity of silver nanoparticles (AgNPs) synthesized from silver nitrate (AgNO3) using aloe vera extract. It was performed by means of incorporating AgNPs on an activated carbon nanoparticle (ACNPs) under ultrasonic agitation (40 kHz, 2 × 50 watt) for 30 min in an aqueous colloidal medium. The successful AgNPs synthesis was clarified with both Ultraviolet-Visible (UV-Vis) and Fourier Transform Infrared (FTIR) spectrophotometers. The successful AgNPs-ACNPs incorporation and its particle size analysis was performed using Transmission Electron Microscope (TEM). The brown color suspension generation and UV-Vis's spectra maximum wavelength at around 480 nm confirmed the existence of AgNPs. The particle sizes of the produced AgNPs were about 5 to 10 nm in the majority number, which collectively surrounded the aloe vera extract secondary metabolites formed core-shell like nanostructure of 8.20 ± 2.05 nm in average size, while ACNPs themselves were about 20.10 ± 1.52 nm in average size formed particles cluster, and 48.00 ± 8.37 nm in average size as stacking of other particles. The antibacterial activity of the synthesized AgNPs and AgNPs-immobilized ACNPs was 57.58% and 63.64%, respectively (for E. coli); 61.25%, and 93.49%, respectively (for S. aureus). In addition, when the AgNPs-immobilized ACNPs material was coated on the cotton and polyester fabrics, the antibacterial activity of the materials changed, becoming 19.23% (cotton; E. coli), 31.73% (polyester; E. coli), 13.36% (cotton; S. aureus), 21.15% (polyester; S. aureus).


Assuntos
Antibacterianos , Carvão Vegetal , Escherichia coli/crescimento & desenvolvimento , Química Verde , Nanopartículas Metálicas/química , Prata , Staphylococcus aureus/crescimento & desenvolvimento , Têxteis , Aloe/química , Antibacterianos/síntese química , Antibacterianos/química , Antibacterianos/farmacologia , Carvão Vegetal/química , Carvão Vegetal/farmacologia , Extratos Vegetais/química , Prata/química , Prata/farmacologia
11.
Molecules ; 26(12)2021 Jun 14.
Artigo em Inglês | MEDLINE | ID: mdl-34198604

RESUMO

Two penta-coordinated [Co(MorphBPT)Cl2]; 1 and [Co(PipBPT)Cl2]; 2 complexes with the bis-pyrazolyl-s-triazine pincer ligands MorphBPT and PipBPT were synthesized and characterized. Both MorphBPT and PipBPT act as NNN-tridentate pincer chelates coordinating the Co(II) center with one short Co-N(s-triazine) and two longer Co-N(pyrazole) bonds. The coordination number of Co(II) is five in both complexes, and the geometry around Co(II) ion is a distorted square pyramidal in 1, while 2 shows more distortion. In both complexes, the packing is dominated by Cl…H, C-H…π, and Cl…C (anion-π stacking) interactions in addition to O…H interactions, which are found only in 1. The UV-Vis spectral band at 564 nm was assigned to metal-ligand charge transfer transitions based on TD-DFT calculations. Complexes 1 and 2 showed higher antimicrobial activity compared to the respective free ligand MorphBPT and PipBPT, which were not active. MIC values indicated that 2 had better activity against S. aureus, B. subtilis, and P. vulgaris than 1. DPPH free radical scavenging assay revealed that all the studied compounds showed weak to moderate antioxidant activity where the nature of the substituent at the s-triazine core has a significant impact on the antioxidant activity.


Assuntos
Antibacterianos/farmacologia , Antioxidantes/farmacologia , Cobalto/química , Complexos de Coordenação/síntese química , Cristalografia por Raios X/métodos , Pirazóis/química , Triazinas/química , Antibacterianos/síntese química , Antioxidantes/química , Complexos de Coordenação/farmacologia , Ligantes , Testes de Sensibilidade Microbiana/métodos , Modelos Moleculares
12.
Chem Commun (Camb) ; 57(62): 7709-7712, 2021 Aug 03.
Artigo em Inglês | MEDLINE | ID: mdl-34259249

RESUMO

Chiral 3-substituted benzoxaboroles were designed as carbapenemase inhibitors and efficiently synthesised via asymmetric Morita-Baylis-Hillman reaction. Some of the benzoxaboroles were potent inhibitors of clinically relevant carbapenemases and restored the activity of meropenem in bacteria harbouring these enzymes. Crystallographic analyses validate the proposed mechanism of binding to carbapenemases, i.e. in a manner relating to their antibiotic substrates. The results illustrate how combining a structure-based design approach with asymmetric catalysis can efficiently lead to potent ß-lactamase inhibitors and provide a starting point to develop drugs combatting carbapenemases.


Assuntos
Antibacterianos/síntese química , Antibacterianos/farmacologia , Proteínas de Bactérias/farmacologia , Benzoxazóis/síntese química , Benzoxazóis/farmacologia , Desenho de Fármacos , Farmacorresistência Bacteriana/efeitos dos fármacos , beta-Lactamases/farmacologia , Antibacterianos/química , Benzoxazóis/química , Técnicas de Química Sintética , Estereoisomerismo
13.
Molecules ; 26(11)2021 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-34206015

RESUMO

New polymer-bioactive compound systems were obtained by immobilization of triazole derivatives onto grafted copolymers and grafted copolymers carrying betaine units based on gellan and N-vinylimidazole. For preparation of bioactive compound, two new types of heterocyclic thio-derivatives with different substituents were combined in a single molecule to increase the selectivity of the biological action. The 5-aryl-amino-1,3,4 thiadiazole and 5-mercapto-1,2,4-triazole derivatives, each containing 2-mercapto-benzoxazole nucleus, were prepared by an intramolecular cyclization of thiosemicarbazides-1,4 disubstituted in acidic and basic medium. The structures of the new bioactive compounds were confirmed by elemental and spectral analysis (FT-IR and 1H-NMR). The antimicrobial activity of 1,3,4 thiadiazoles and 1,2,4 triazoles was tested on gram-positive and gram-negative bacteria. The triazole compound was chosen to be immobilized onto polymeric particles by adsorption. The Langmuir, Freundlich, and Dubinin-Radushkevich adsorption isotherm were used to describe the adsorption equilibrium. Also, the pseudo-first and pseudo-second models were used to elucidate the adsorption mechanism of triazole onto grafted copolymer based on N-vinylimidazole and gellan (PG copolymer) and grafted copolymers carrying betaine units (PGB1 copolymer). In vitro release studies have shown that the release mechanism of triazole from PG and PGB1 copolymers is characteristic of an anomalous transport mechanism.


Assuntos
Antibacterianos/síntese química , Betaína/química , Polissacarídeos Bacterianos/química , Triazóis/síntese química , Antibacterianos/química , Antibacterianos/farmacologia , Bacillus cereus/efeitos dos fármacos , Bacillus subtilis/efeitos dos fármacos , Ciclização , Escherichia coli/efeitos dos fármacos , Testes de Sensibilidade Microbiana , Salmonella enteritidis/efeitos dos fármacos , Staphylococcus aureus/efeitos dos fármacos , Triazóis/química , Triazóis/farmacologia
14.
Eur J Med Chem ; 222: 113580, 2021 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-34116324

RESUMO

In search of novel therapeutic agents active against emerging drug-resistant Mycobacterium tuberculosis and to counter the long treatment protocol of existing drugs, herein we present synthesis and biological evaluation of a new series of 5-phenyl-3-isoxazolecarboxylic acid methyl ester-chalcone hybrids. Among 35 synthesized compounds, 32 analogues displayed potent in-vitro activity against Mycobacterium tuberculosis H37Rv with MIC 0.12-16 µg/mL. Cell viability test against Vero cells indicated 29 compounds to be non-cytotoxic (CC50 > 20 µg/mL & SI > 10). Most potent compounds with MIC 0.12 µg/mL (7 b, 7j, 7 ab) exhibited selectivity index (SI) in excess of 320. Further studies on activity against drug-resistant Mycobacterium tuberculosis revealed 7j as the most potent compound with MIC 0.03-0.5 µg/mL. Time-kill kinetic study suggested compound 7j displaying concentration-dependent bactericidal killing activity with relatively comparable potency to that of current first-line anti-TB drugs. Taken together, 7j presents a novel hit with potential to be translated into a potent antimycobacterial.


Assuntos
Antibacterianos/farmacologia , Chalcona/farmacologia , Farmacorresistência Bacteriana/efeitos dos fármacos , Ésteres/farmacologia , Isoxazóis/farmacologia , Mycobacterium tuberculosis/efeitos dos fármacos , Antibacterianos/síntese química , Antibacterianos/química , Chalcona/química , Relação Dose-Resposta a Droga , Ésteres/química , Isoxazóis/química , Testes de Sensibilidade Microbiana , Estrutura Molecular , Relação Estrutura-Atividade
15.
Eur J Med Chem ; 222: 113628, 2021 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-34139627

RESUMO

The increasing resistance of methicillin-resistant Staphylococcus aureus (MRSA) to antibiotics has led to a growing effort to design and synthesize novel structural candidates of chalcone-conjugated, multi-flexible end-group coumarin thiazole hybrids with outstanding bacteriostatic potential. Bioactivity screening showed that hybrid 5i, which was modified with methoxybenzene, exerted a significant inhibitory activity against MRSA (MIC = 0.004 mM), which was 6 times better than the anti-MRSA activity of the reference drug norfloxacin (MIC = 0.025 mM). Compound 5i neither conferred apparent resistance onto MRSA strains even after multiple passages nor triggered evident toxicity to human hepatocyte LO2 cells and normal mammalian cells (RAW 264.7). Molecular docking showed that highly active molecule 5i might bind to DNA gyrase by forming stable hydrogen bonds. In addition, molecular electrostatic potential surfaces were developed to explain the high antibacterial activity of the target compounds. Furthermore, preliminary mechanism studies suggested that hybrid 5i could disrupt the bacterial membrane of MRSA and insert itself into MRSA DNA to impede its replication, thus possibly becoming a potential antibacterial repressor against MRSA.


Assuntos
Antibacterianos/farmacologia , Chalconas/farmacologia , Cumarínicos/farmacologia , Staphylococcus aureus Resistente à Meticilina/efeitos dos fármacos , Tiazóis/farmacologia , Animais , Antibacterianos/síntese química , Antibacterianos/química , Linhagem Celular , Chalconas/química , Cumarínicos/química , Relação Dose-Resposta a Droga , Humanos , Camundongos , Testes de Sensibilidade Microbiana , Simulação de Acoplamento Molecular , Estrutura Molecular , Relação Estrutura-Atividade , Tiazóis/química
16.
Eur J Med Chem ; 222: 113600, 2021 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-34144355

RESUMO

Cancer and antibiotic resistance are two global health threats that usually hamper clinical chemotherapeutic efficacy. Particularly for lung cancer, bacterial infections frequently arise thereby complicating the course of cancer treatment. In this sense, three new neutral luminescent cycloplatinated(II) photosensitizers of the type [Pt(dmba)(L)] (dmba = N,N-dimethylbenzylamine-κN,κC; L = 2-(benzo[d]oxazol-2-yl)-phenolato-κN,κO1, 2-(benzo[d]thiazol-2-yl)-phenolato-κN,κO2, and 2-(1-methyl-1H-benzo[d]imidazole-2-yl)phenolato-κN,κO3) have been characterized and developed to potentially eliminate both resistant bacteria and lung cancer cells. The phototherapeutic effects of complex 2 have been evaluated using low doses of blue light irradiation. Complex 2 exerted promising photoactivity against pathogenic Gram-positive bacteria strains of clinical interest, displaying a phototoxic index (PI) of 15 for methicillin-resistant Staphylococcus aureus, one of the major microorganisms predominating lung infections. Likewise, the anticancer activity of 2 was also increased upon light irradiation in human lung A549 cancer cells (PI = 36). Further in vitro experiments with this platinum(II) complex suggest that ROS-generating photodynamic reactions were involved upon light irradiation, thus providing a reasonable mechanism for its dual anticancer and antibacterial activities.


Assuntos
Antibacterianos/farmacologia , Antineoplásicos/farmacologia , Infecções Bacterianas/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Staphylococcus aureus Resistente à Meticilina/efeitos dos fármacos , Compostos Organoplatínicos/farmacologia , Fármacos Fotossensibilizantes/farmacologia , Antibacterianos/síntese química , Antibacterianos/química , Antineoplásicos/síntese química , Antineoplásicos/química , Relação Dose-Resposta a Droga , Humanos , Neoplasias Pulmonares/microbiologia , Estrutura Molecular , Compostos Organoplatínicos/síntese química , Compostos Organoplatínicos/química , Fármacos Fotossensibilizantes/síntese química , Fármacos Fotossensibilizantes/química , Relação Estrutura-Atividade
17.
J Med Chem ; 64(12): 8644-8665, 2021 06 24.
Artigo em Inglês | MEDLINE | ID: mdl-34080858

RESUMO

Due to the poor permeability across Gram-negative bacterial membranes and the troublesome bacterial efflux mechanism, only a few GyrB/ParE inhibitors with potent activity against Gram-negative pathogens have been reported. Among them, pyrimido[4,5-b]indole derivatives represented by GP-1 demonstrated excellent broad-spectrum antibacterial activity against both Gram-positive and Gram-negative bacteria but were limited by hERG inhibition and poor pharmacokinetics profile. To improve their drug-like properties, we designed a series of novel pyrimido[4,5-b]indole derivatives based on the tricyclic scaffold of GP-1 and the C-7 moiety of acorafloxacin. These efforts have culminated in the discovery of a promising compound 18r with reduced hERG liability and an improved PK profile. Compound 18r exhibited superior broad-spectrum in vitro antibacterial activity compared to GP-1, including a variety of clinical multidrug G- pathogens, especially Acinetobacter baumannii, and the in vivo efficacy was also demonstrated in a neutropenic mouse thigh model of infection with multidrug-resistant A. baumannii.


Assuntos
Infecções por Acinetobacter/tratamento farmacológico , Antibacterianos/uso terapêutico , Bactérias/efeitos dos fármacos , Indóis/uso terapêutico , Pirimidinas/uso terapêutico , Animais , Antibacterianos/síntese química , Antibacterianos/metabolismo , Antibacterianos/farmacocinética , DNA Girase/metabolismo , Desenho de Fármacos , Farmacorresistência Bacteriana Múltipla/efeitos dos fármacos , Estabilidade de Medicamentos , Células HEK293 , Humanos , Indóis/síntese química , Indóis/metabolismo , Indóis/farmacocinética , Testes de Sensibilidade Microbiana , Microssomos Hepáticos/metabolismo , Simulação de Acoplamento Molecular , Estrutura Molecular , Pirimidinas/síntese química , Pirimidinas/metabolismo , Pirimidinas/farmacocinética , Ratos , Relação Estrutura-Atividade
18.
J Enzyme Inhib Med Chem ; 36(1): 1217-1229, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-34080514

RESUMO

The thiazolidinone ring is found in compounds that have widespan biology activity and there is mechanism-based evidence that compounds bearing this moiety inhibit P. aeruginosa PhzS (PaPzhS), a key enzyme in the biosynthesis of the virulence factor named pyocyanin. Ten novel thiazolidinone derivatives were synthesised and screened against PaPhzS, using two orthogonal assays. The biological results provided by these and 28 other compounds, whose synthesis had been described, suggest that the dihydroquinazoline ring, found in the previous hit (A- Kd = 18 µM and LE = 0.20), is not required for PaPzhS inhibition, but unsubstituted nitrogen at the thiazolidinone ring is. The molecular simplification approach, pursued in this work, afforded an optimised lead compound (13- 5-(2,4-dimethoxyphenyl)thiazolidine-2,4-dione) with 10-fold improvement in affinity (Kd= 1.68 µM) and more than 100% increase in LE (0.45), which follows the same inhibition mode as the original hit compound (competitive to NADH).Executive summaryPhzS is a key enzyme in the pyocyanin biosynthesis pathway in P. aeruginosa.Orthogonal assays (TSA and FITC) show that fragment-like thiazolidinedione derivatives bind to PaPhzS with one-digit micromolar affinity.Fragment-like thiazolidinedione derivatives bind to the cofactor (NADH) binding site in PaPhzS.The molecular simplification optimised the ligand efficiency and affinity of the lead compound.


Assuntos
Antibacterianos/síntese química , Antibacterianos/farmacologia , Pseudomonas aeruginosa/efeitos dos fármacos , Tiazolidinedionas/farmacologia , Humanos , Ligantes , Tiazolidinedionas/síntese química
19.
J Med Chem ; 64(13): 9141-9151, 2021 07 08.
Artigo em Inglês | MEDLINE | ID: mdl-34182755

RESUMO

In an attempt to exploit the hydrolytic mechanism by which ß-lactamases degrade cephalosporins, we designed and synthesized a series of novel cephalosporin prodrugs aimed at delivering thiol-based inhibitors of metallo-ß-lactamases (MBLs) in a spatiotemporally controlled fashion. While enzymatic hydrolysis of the ß-lactam ring was observed, it was not accompanied by inhibitor release. Nonetheless, the cephalosporin prodrugs, especially thiomandelic acid conjugate (8), demonstrated potent inhibition of IMP-type MBLs. In addition, conjugate 8 was also found to greatly reduce the minimum inhibitory concentration of meropenem against IMP-producing bacteria. The results of kinetic experiments indicate that these prodrugs inhibit IMP-type MBLs by acting as slowly turned-over substrates. Structure-activity relationship studies revealed that both phenyl and carboxyl moieties of 8 are crucial for its potency. Furthermore, modeling studies indicate that productive interactions of the thiomandelic acid moiety of 8 with Trp28 within the IMP active site may contribute to its potency and selectivity.


Assuntos
Antibacterianos/farmacologia , Cefalosporinas/farmacologia , Inibidores de beta-Lactamases/farmacologia , beta-Lactamases/metabolismo , Antibacterianos/síntese química , Antibacterianos/química , Cefalosporinas/síntese química , Cefalosporinas/química , Relação Dose-Resposta a Droga , Estrutura Molecular , Relação Estrutura-Atividade , Inibidores de beta-Lactamases/síntese química , Inibidores de beta-Lactamases/química
20.
Top Curr Chem (Cham) ; 379(4): 29, 2021 Jun 10.
Artigo em Inglês | MEDLINE | ID: mdl-34109453

RESUMO

This review concentrates on recent developments in ruthenium Schiff bases, whose steric and electronic characteristics can be manipulated easily by selecting suitable condensing aldehydes or ketones and primary amines, and their metal complexes. Ruthenium metal-based complexes and Schiff base ligands are rapidly becoming conventionally considered for biological applications (antioxidant, anticancer, antimicrobial), in catalysis, in functional materials, in sensors, and as pigments for dyes. Ruthenium complexes exhibit a broad variety of activities concerning simple Schiff base ligands. This may be due to the octahedral bonding of both Ru(II) and Ru(III) complexes, which acquire an extended reservoir of a three-dimensional framework, providing the potential for an elevated degree of site selectivity for binding to their biological targets. This review provides an overview of this field, and intends to highlight both ligand design and synthetic methodology development, as well as significant applications of these metal complexes. In this review, we summarize our work on the development of ruthenium complexes, which was performed over the last few years.


Assuntos
Compostos de Rutênio/síntese química , Compostos de Rutênio/farmacologia , Bases de Schiff , Antibacterianos/síntese química , Antibacterianos/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Antioxidantes/síntese química , Antioxidantes/farmacologia , Desenho de Fármacos
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