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Abstract: Antibiotic resistance can be characterized, in biochemical terms, as an antibiotic’s inability to reach its bacterial target at a concentration that was previously effective. Microbial resistance to different agents can be intrinsic or acquired. Intrinsic resistance occurs due to inherent functional or structural characteristics of the bacteria, such as antibiotic-inactivating enzymes, nonspecific efflux pumps, and permeability barriers. On the other hand, bacteria can acquire resistance mechanisms via horizontal gene transfer in mobile genetic elements such as plasmids. Acquired resistance mechanisms include another category of efflux pumps with more specific substrates, which are plasmid-encoded. Efflux pumps are considered one of the main mechanisms of bacterial resistance to antibiotics and biocides, presenting themselves as integral membrane transporters. They are essential in both bacterial physiology and defense and are responsible for exporting structurally diverse substrates, falling into the following main families: ATP-binding cassette (ABC), multidrug and toxic compound extrusion (MATE), major facilitator superfamily (MFS), small multidrug resistance (SMR) and resistance-nodulation-cell division (RND). The Efflux pumps NorA and Tet(K) of the MFS family, MepA of the MATE family, and MsrA of the ABC family are some examples of specific efflux pumps that act in the extrusion of antibiotics. In this review, we address bacterial efflux pump inhibitors (EPIs), including 1,8-naphthyridine sulfonamide derivatives, given the pre-existing knowledge about the chemical characteristics that favor their biological activity. The modification and emergence of resistance to new EPIs justify further research on this theme, aiming to develop efficient compounds for clinical use.

Aiming to valorise the Atlantic Rainforest biodiversity in Santa Catarina, the chemical characterisation of the essential oils (EOs) from leaves of Vernonanthura montevidensis (Spreng.) H. Rob. is described for the first time. Fresh leaves collected in the year 2014 and 2015, were submitted to hydrodistillation to give pale blue EOs in yields of 0.21 and 0.19%, respectively. The EOs were characterised by GC-MS and GC-FID semi- and quantitative methods. The monoterpene β-pinene was the major constituent in both samples reaching a maximum of 26.3%. The monoterpene α-pinene and the sesquiterpene β-caryophyllene, were also among the major constituents in both samples. By means of the extracted ion chromatogram procedure, it was possible to detect chamazulene, which was associated with the pale blue colour of the essential oils. In the in vitro antimollicute assays, the essential oil was moderately active against Mycoplasma genitalium and M. pneumoniae with MIC values of 250 µg mL−1.

This study aimed to evaluate the intrinsic antibacterial activity and antibiotic-enhancing effect of an arylamino methylene derivative (MAD) in association with fluoroquinolones. The antibacterial activity against multiresistant Pseudomonas aeruginosa, Staphylococcus aureus and Escherichia coli was analyzed by determining the minimum inhibitory concentration (MIC) using the broth micro dilution method. A reduction in the MIC of the fluoroquinolones against strains treated simultaneously with the MAD was interpreted as an enhanced antibiotic activity. While the MAD exhibited no clinically effective action (MIC ≥ 1.024 µg/mL), it was found to significantly potentiate the activity of norfloxacin, ofloxacin and lomefloxacin against all the strains, which may be related to structural similarities between the MAD and quinolones. Our findings suggest that Meldrum’s acid arylamino derivatives may represent promising molecules in the elaboration of new drugs to reverse resistance to fluoroquinolones.

Aiming to valorise the Atlantic Rainforest biodiversity in Santa Catarina, the chemical characterisation of the essential oils (EOs) from leaves of

Objective Efflux pumps are transmembrane proteins associated with bacterial resistance mechanisms. Bacteria use these proteins to actively transport antibiotics to the extracellular medium, preventing the pharmacological action of these drugs. This study aimed to evaluate in vitro the antibacterial activity of 1,8-naphthyridines sulfonamides, as well as their ability to inhibit efflux systems of Staphylococcus aureus strains expressing different levels of the NorA efflux pump. Methods The broth microdilution test was performed to assess antibacterial activity. Efflux pump inhibition was evaluated in silico by molecular docking and in vitro by fluorometric tests, and the minimum inhibitory concentration (MIC) was determined. The MIC was determined in the association between 1,8-naphthyridine and norfloxacin or ethidium bromide. Results The 1,8-naphthyridines did not show direct antibacterial activity. However, they effectively reduced the MIC of multidrug-resistant bacteria by associating with norfloxacin and ethidium bromide, in addition to increasing the fluorescence emission. In silico analysis addressing the binding between NorA and 1,8-naphthyridines suggests that hydrogen bonds and hydrophilic interactions represent the interactions with the most favourable binding energy, corroborating the experimental data. Conclusion Our data suggest that 1,8-naphthyridines sulfonamides inhibit bacterial resistance through molecular mechanisms associated with inhibition of the NorA efflux pump in S. aureus strains.

The secular use of plants in popular medicine has emerged as a source for the discovery of new compounds capable of curing infections. Among microbial resistance to commercial drugs, species such as Piper diospyrifolium Kunth, which are used in popular therapy, are targets for pharmacological studies. With this in mind, antimicrobial experiments with the essential oil from the P. diospyrifolium (PDEO) species were performed and its constituents were elucidated. The oil compounds were identified by gas chromatography coupled to mass spectrometry (GC/MS). The broth microdilution method with colorimetric readings for bacterial tests (Escherichia coli and Staphylococcus aureus) and spectrophotometric readings for fungal tests (Candida albicans and Candida tropicalis), whose data were used to create a cell viability curve and calculate its IC50 against fungal cells, were used to determine the minimum inhibitory concentration of the oil and its combined action with commercial drugs. The oil's minimal fungicidal concentration and its action over fungal morphological transition were analyzed by subculture and microculture, respectively. Chemical analysis revealed Z-Carpacin, Pogostol and E-Caryophyllene as the most abundant compounds. Results from the intrinsic analysis were considered clinically irrelevant, however the oil presented a synergistic effect against multiresistant E. coli and S. aureus strains when associated with gentamicin, and against the standard and isolated C. tropicalis strains with fluconazole. A fungicidal effect was observed against the C. albicans isolate. Candida spp. hyphae inhibition was verified for all strains at the highest tested concentrations. The P. diospyrifolium essential oil presented a promising effect when associated with commercial drugs and against a fungal virulence factor. Thus, the oil presented active compounds which may help the development of new drugs, however, new studies are needed in order to clarify the oil's mechanism of action, as well as to identify its active constituents.

This study aimed to evaluate the antibacterial activity and to verify, in silico and in vitro, the inhibition of efflux mechanisms using a series of synthesized 1,8-naphthyridines sulfonamides against Staphylococcus aureus strains carrying MepA efflux pumps. The chemical synthesis occurred through the thermolysis of the Meldrum's acid adduct. The sulfonamide derivatives were obtained by the sulfonylation of 2-amino-5‑chloro-1,8-naphthyridine with commercial benzenesulfonyl chloride. Antibacterial activity was assessed by the broth microdilution test. Efflux pump inhibitory capacity was evaluated in silico by molecular docking and in vitro by analyzing synergistic effects on ciprofloxacin and ethidium bromide (EtBr) and by EtBr fluorescence emission assays. The following 1,8-naphthyridines were synthesized: 4-methyl-N-(5‑chloro-1,8-naphthyridin-2-yl)-benzenesulfonamide (Compound 10a); 2,5-dichloro-N-(5‑chloro-1,8-naphthyridin-2-yl)-benzenesulfonamide (Compound 10b); 4-fluoro-N-(5‑chloro-1,8-naphthyridin-2-yl)-benzenesulfonamide (Compound 10c); 2,3,4-trifluoro-N-(5‑chloro-1,8-naphthyridin-2-yl)-benzenesulfonamide (Compound 10d); 3-trifluoromethyl-N-(5‑chloro-1,8-naphthyridin-2-yl)-benzenesulfonamide (Compound 10e); 4‑bromo-2,5-difluoro-N-(5‑chloro-1,8-naphthyridin-2-yl)-benzenesulfonamide (Compound 10f). The 1,8-naphthyridines derivatives associated with sulfonamides did not show antibacterial activity. However, they showed a favorable pharmacokinetic profile with possible MepA efflux pump inhibitory action, demonstrated in molecular docking. In addition to the promising results in reducing the concentration of intracellular EtBr. 1,8-naphthyridines act as putative agents in the inhibitory action of the MepA efflux pump.

Naphthyridines represent a class of heterocyclic compounds formed by two condensed aromatic rings. This study aimed to evaluate the antibacterial activity and in vitro inhibition of efflux resistance mechanisms of a series of 1,8-naphthyridine sulfonamides against strains carrying Tet(K) and MsrA efflux pumps. The efflux pump inhibitory capacity was evaluated by analyzing synergistic effects between 1,8-naphthyridine sulfonamides and standard antibiotics, as well as ethidium bromide. The following 1,8-naphthyridines were used: 4-methyl-N-(5-chloro-1,8-naphthyridin-2-yl)-benzenesulfonamide (Naph 1); 2,5-Dichloro-N-(5-chloro-1,8-naphthyridin-2-yl)-benzenesulfonamide (Naph 2); 2,3,4-trifluoro-N-(5-chloro-1,8-naphthyridin-2-yl)benzenesulfonamide (Naph 7); 3-trifluoromethyl-N-(5-chloro-1,8-naphthyridin-2-yl)-benzenesulfonamide (Naph 9). The 1,8-naphthyridine sulfonamide derivatives possessed a potential Tet(K) and MsrA efflux pump inhibitory action.

Infections by multiresistant microorganisms have led to a continuous investigation of substances acting as modifiers of this resistance. By following this approach, the chemical composition of the essential oil from Piper caldense leaf and its antimicrobial potential were investigated. The antimicrobial activity was determined by broth microdilution method providing values for minimum inhibitory concentration (MIC), IC50, and minimum fungicidal concentration (MFC). The essential oil was tested as a modulator for several antibiotics, and its effect on the morphology of Candida albicans (CA) strains was also investigated. The chemical characterization revealed an oil composed mainly of sesquiterpenes. Among them are caryophyllene oxide (13.9%), spathulenol (9.1%), &delta, cadinene (7.6%) and bicyclogermacrene (6.7%) with the highest concentrations. The essential oil showed very low activity against the strains of CA with the lowest values for IC50 and MFC of 1790 &mu, g/mL and 8192 &mu, g/mL, respectively. The essential oil modulated the activity of fluconazole against CA URM 4387 strain, which was demonstrated by the lower IC50 obtained, 2.7 &mu, g/mL, whereas fluconazole itself presented an IC50 of 7.76 &mu, g/mL. No modulating effect was observed in the MFC bioassays. The effect on fungal morphology was observed for both CA INCQS 40006 and URM 4387 strains. The hyphae projection was completely inhibited at 4096 &mu, g/mL and 2048 &mu, g/mL, respectively. Thus, the oil has potential as an adjuvant in antimicrobial formulations.

The Piper mikanianum species were investigated by the antimicrobial potential and chemical composition. Chemical analysis was performed by gas chromatography coupled to mass spectrometry (GC/MS). The Minimum Inhibitory Concentration (MIC) as well as the 50% Inhibitory Concentration against Candida strains were determined by microdilution. The effect of the drug-oil combination was also evaluated to verify possible synergism. The Minimum Fungicidal Concentration (MFC) was evaluated by subculturing the microdilution in Petri dishes and the anti-pleomorphism potential of the oil was tested in humid chambers. Chemical analysis revealed safrol as the major compound. The results from the intrinsic activity evaluation of the oil did not reveal a clinical importance, however, it presented a synergistic effect when associated with gentamicin against the multidrug resistant E. coli strain and when associated with fluconazole against fungal strains. Moreover, the oil possessed a fungistatic effect. Total inhibition of filamentous structures occurred in both Candida species in the anti-virulence test. The P. mikanianum essential oil showed a potentiating activity of drugs for which resistance exists and an inhibitory effect of one of the main virulence factors of the Candida genus, morphological transition, which has been previously shown to be responsible for causing invasive infections in human tissues.

Due to the biological properties associated to the Baccharis genus and the limited information on its antimicrobial properties, the present work investigates the chemical composition and antibacterial, antifungal and antiprotozoal activities of the essential oils of two species, B. uncinella from Campo Alegre and B. semiserrata from Atalanta, both places located in Santa Catarina State, Southern Brazil. Oils were obtained by hydrodistillation and were analyzed by gas chromatography–flame ionization detector (GC–FID) and GC–mass spectrometry (GC–MS). The dry leaf essential oil yield from B. uncinella was 0.65% (m/m), and 0.50% and 0.22% (m/m) for dry leaf and twig from B. semiserrata, respectively. The main components in the oil from B. uncinella were α-pinene (9.0%), β-pinene (9.2%), limonene (11.5%), β-caryophyllene (13.2%) and spathulenol (9.3%). The following major compounds were identified in the leaf essential oil from B. semiserrata: α-pinene (4.3%), β-pinene (11.4%), limonene (6.7%), β-caryophyllen...

In our continuous search for naturally occurring compounds of scientific and technological relevance, the chemical composition and antibacterial activity of the essential oils of two populations of Piper xylosteoides from Santa Catarina, Brazil, is described. Both oils showed a very high safrole concentration, being the highest value associated to the sample collected in Orleans (84.1%). As the second major compound, the monoterpene α-pinene was present with the highest concentration (15.3%) in the Sao Bonifacio sample. The antibacterial activity was examined towards both Gram-positive and Gram-negative bacteria. The oils showed weak activity against the bacteria tested. This species can be considered a new economically important natural source of the arylpropanoid safrole.

Two 1,8-naphthyridines were synthesized and found to be fluorescent in solution. These compounds were studied in the presence of Cu + and Cu 2+ ions and it was verified that the metal causes the quenching of their fluo- rescence emission, due to the formation of complexes be- tween the naphthyridine and the metal. A displacement assay was carried out in a DMSO-water mixture with the addition of various anions to the solutions of the complexes, and it was observed that these systems have a high capacity to selectively detect cyanide.

The influence of the bridging group between the mesogenic group and the terminal position on liquid-crystalline behavior was investigated. Two liquid-crystalline series containing pentagonal heterocycles were synthesized for this purpose. The liquid-crystal phase of mesogens with the isoxazole group was more stable than that of those with isoxazole and tetrazole groups in the same molecule. The mesogens with only the isoxazole group showed better thermal properties than those with isoxazoles and tetrazoles. Nematic and smectic phases were observed. The mesophase sequences of the materials were investigated by polarization microscopy and DSC (Differential Scanning Calorimetry).

The new 5-(n-alkoxyphenyl)-2-n-alkyltetrazole (L¹) and alpha,omega-bis-[5-(4-pentoxyphenyl)-2-alkanetetrazoles] (L²) ligands and their Pd(II) complexes have been synthesized. The X-ray diffraction study of the palladium complex with L¹ reveals a mononuclear structure in which the geometry of the Pd(L¹)2Cl2 chromophore is planar as required by the inversion center at the palladium atom, where each molecule of phenyltetrazole binds to the metal ion in a monodentate fashion via a Pd-N1 sigma-bond. For the palladium complex with L², a dinuclear structure ([Pd2(L²)2Cl4 ]) has been proposed on the basis of NMR and IR spectroscopy. Neste trabalho, descreve-se a síntese de novos ligantes e dos seus complexos de Pd(II) com os ligantes 5-(n-alcoxifenil)-2-n-alquiltetrazol (L¹) e alfa,ômega-bis-[5-(4-pentoxifenil)-2-alcanotetrazois] (L²). A determinação estrutural através de difração de raios-X do complexo de paládio contendo L¹ revela uma estrutura mononuclear na qual a geometria do cromóforo Pd(L¹)2Cl2 é plana e possui um centro de inversão sobre o átomo de paládio. As moléculas de feniltetrazol estão ligadas ao íon metálico de forma monodentada e trans entre si, através de uma ligação sigma, Pd-N1. Para o complexo de paládio contendo L², propõe-se uma estrutura dinuclear, ([Pd2(L²)2Cl4 ]), com base em dados de espectroscopia de RMN e IV.

Essential oils have been extensively studied in recent years as a natural source of new antimicrobial agents. In this work, essential oils of leaf and branch from Drimys angustifolia growing in Southern Brazil were obtained by hydrodistillation and analyzed by gas chromatographies with flame ionization detector (GC-FID) and with mass spectrometer (GC-MS). Drimenol and bicyclogermacrene were isolated by column chromatography from branch and leaf essential oils, respectively. Oils, isolated compounds and combinations of them were assayed against Gram-(+) and Gram-(-) bacteria. The oils showed to be more active against Bacillus cereus, with minimum inhibitory concentration (MIC) 125 and 250 µg mL-1 for branch and leaf oils, respectively, strongly inhibiting bacterial growth. Bicyclogermacrene was more active then drimenol, providing a MIC value of 167 µg mL-1 against B. cereus. Synergism was not observed in any of the combinations tested. Nos últimos anos, os óleos essenciais vêm sendo intensamente estudados como fonte natural de novos agentes antimicrobianos. Neste trabalho, os óleos essenciais das folhas e galhos de Drimys angustifolia do sul do Brasil foram obtidos por hidrodestilação e analisados por cromatografias gasosas com detector de ionização de chama (GC-FID) e com espectrômetro de massa (GC-MS). Os constituintes drimenol e biciclogermacreno foram isolados por cromatografia em coluna do óleo essencial dos galhos e folhas, respectivamente. Os óleos, os constituintes isolados e combinações destes foram testados contra bactérias Gram-(+) e Gram-(-). Os óleos essenciais foram mais ativos contra Bacillus cereus, com MIC (concentração inibitória mínima) de 125 e 250 µg mL-1 para os galhos e folhas, respectivamente, inibindo fortemente o crescimento bacteriano. Biciclogermacreno foi mais ativo que drimenol, fornecendo um valor de MIC de 167 µg mL-1 contra B. cereus. Não foi observado qualquer efeito sinérgico nas combinações testadas.

Homologues series of some derivatives of 3,5-(4-substituted phenyl)-1,2,4-oxydiazole were synthesized and their phase behavior studied. Introduction of the pentagonal heteroaromatic ring leads to significant changes in mesomorphic behavior in comparison with analogous compounds containing the phenyl ring. The synthesised compounds exhibit smectic and nematic phases.

According to the Health’s World Organization, leishmaniasis and trypanossomiasis are growing problems of public health, being endemic particularly in Latin America. The medicines utilized in the handling of these illnesses were developed many decades ago, and they show a low efficacy and strong side effects. The pyridoquinolines are heterocyclic diazaantracenic compounds that have showed cytotoxic activity. The biological importance of the pyridoquinolines, and the interest in discovering new leishmanicides and trypanocides agents have been stimulating the synthesis of substituted pyrido[2,3–g]quinolines, and the evaluation of their leishmanicide and trypanocide potential. So, this work describes the diazatricicles’s synthesis, using the termociclization’s reaction of the fenilenediaminic bis-adduct of Meldrum’s acid. The 2,5-dimethyl-1,4-bis[(2,2-dimethyl-4,6-dioxo-1,3-dioxane-5-ylidenomethyl)amino]-benzene has been obtained in good yield by the condensation of the Meldrum’s acid with the 2,5-dimethyl-1,4-phenylenediamine in trimethylorthoformate. The termociclization in diphenylether has been accompanied for a spontaneous elimination of acetone and carbon dioxide generating the diazatricycle, that has been chlorinated without prior purification with phosphorus oxichloride, giving the 4,9-dichloro-5,10-dimethyl-pyrido[2,3-g]quinoline, in low yield. The nucleophilic substitution’s reaction with the 2-amine-5-diethylaminepentane has been repeated several times in different reaction’s conditions, but we haven’t obtained the expected product, needing the search of new procedures and optimization of the reaction’s conditions. The obtained compounds have been characterized by spectroscopic technicals of IV and RMN 1H. The evaluation of the leishmanicide and trypanocide activity was done for the compound called 4,9-dichloro-5,10-dimethyl-pyrido[2,3-g]quinoline, however it hasn’t even presented any activity

The title compound, C 7 H 6 N 4 O.1.5H 2 O, is a key intermediate in the synthesis of mesogens, which are derivatives of phenyltetrazole. The tetrazole and phenyl rings are planar to within 0.007 (2) A, with a dihedral angle of 14.8 (1)° between the planes.