Azoalkyl ether imidazo[2,1-b]benzothiazoles as potentially antimicrobial agents with novel structural skeleton

A series of new azoalkyl ether imidazo[2,1-b]benzothiazoles were developed via a convenient synthetic procedure. The antimicrobial assays showed that a good number of the prepared derivatives exhibited significant inhibitory properties against most of the tested strains. Especially 2-methyl-5-nitroimidazole derivative 5a presented superior inhibit activity against MRSA and B. typhi with MIC?=?4?μg/mL and MIC?=?1?μg/mL, respectively. The highly active compound 5a showed low toxicity against mammalian cells without obvious triggering of the development of bacterial resistance, and it also possessed rapid bactericidal efficacy. Molecular docking study exposed that the active molecule 5a could interact with the active site of S. aureus gyrase through hydrogen bond. Quantum chemical studies were also performed to explain the high antibacterial activity. Further investigation revealed that compound 5a could significantly associate with gyrase–DNA complex by mean of hydrogen bonds and could efficiently intercalate into MRSA DNA to form 5a–DNA supramolecular complex, which impart potent bioactivity.     

3-Hydroxy-1,5-dihydro-2H-pyrrol-2-ones as novel antibacterial scaffolds against methicillin-resistant Staphylococcus aureus

Herein, we report the synthesis and evaluation of 3-hydroxy-1,5-dihydro-2H-pyrrol-2-ones as antibacterial agents against methicillin-resistant S. aureus (MRSA) and methicillin-resistant S. epidermidis (MRSE). Lead compound 38 showed minimum inhibitory concentrations (MICs) of 8 and 4?μg/mL against MRSA and MRSE, respectively. Furthermore, compound 38 displayed a MIC of 8–16?μg/mL against linezolid-resistant MRSA. These molecules, previously underexplored as antibacterial agents, serve as a new scaffold for antimicrobial development.     

Photo-Irradiation of Proanthocyanidin as a New Disinfection Technique via Reactive Oxygen Species Formation

In the present study, the bactericidal effect of photo-irradiated proanthocyanidin was evaluated in relation to reactive oxygen species formation. Staphylococcus aureus suspended in proanthocyanidin aqueous solution was irradiated with light from a laser at 405 nm. The bactericidal effect of photo-irradiated proanthocyanidin depended on the concentration of proanthocyanidin, the laser irradiation time, and the laser output power. When proanthocyanidin was used at the concentration of 1 mg/mL, the laser irradiation of the bacterial suspension could kill the bacteria with a >5-log reduction of viable cell counts. By contrast, bactericidal effect was not observed when proanthocyanidin was not irradiated. In electron spin resonance analysis, reactive oxygen species, such as hydroxyl radicals, superoxide anion radicals, and hydrogen peroxide, were detected in the photo-irradiated proanthocyanidin aqueous solution. The yields of the reactive oxygen species also depended on the concentration of proanthocyanidin, the laser irradiation time, and the laser output power as is the case with the bactericidal assay. Thus, it is indicated that the bactericidal effect of photo-irradiated proanthocyanidin is exerted via the reactive oxygen species formation. The bactericidal effect as well as the yield of the oxygen radicals increased with the concentration of proanthocyanidin up to 4 mg/mL, and then decreased with the concentration. These findings suggest that the antioxidative activity of proanthocyanidin might prevail against the radical generation potency of photo-irradiated proanthocyanidin resulting in the decreased bactericidal effect when the concentration is over 4 mg/mL. The present study suggests that photo-irradiated proanthocyanidin whenever used in an optimal concentration range can be a new disinfection technique.     

Convenient framework of poly functionalized (E)-2-benzylideno-(Z)-carbazolylideno cyanoacetamides via rearrangements as an efficient antibiofilm inhibitors with SAR study

A simple and one-pot approach for the synthesis of highly functionalized novel (E)-2-benzylideno-(Z)-carbazolylideno cyanoacetamide derivatives from different 2-(2′,3′,4′,9′-tetrahydro-carbazol-1′-ylidene)-propanedinitriles and aryl/heteroaryl carbaldehydes via vinylogous aldol reaction. The structures of the molecules were designated by FT-IR, ¹H NMR, ¹³C NMR studies, elemental and X-ray crystallographic analysis. The synthesized pure products have been screened for in vitro antibiofilm inhibitory activity towards antibiotic-resistant pathogenic organisms. All the synthesized compounds showed biofilm inhibition. Promisingly, the moieties 3a, 3d and 3h showed higher antibiofilm activity at biofilm inhibitory concentration (BIC) (200?μg/mL) against bacterial pathogens. Among the three moieties, 3a showed high prospective against E. coli biofilm with minimal and maximal BIC percentage of 32% (10?μg/mL) and 89% (100?μg/mL) and chosen lowest BIC for further evaluation. Also, the 3a generate ROS two fold at 1?h treatment in E. coli biofilm. The 3a exhibited no toxic effect on cell viability upto 75?μg/mL in HEK293 cell lines. The results of the present study reveal that among (E)-2-benzylideno-(Z)-carbazolylideno cyanoacetamides, (E)-2-benzylideno-6-methyl-2,3,4,9-tetrahydro-1H-carbazol-(Z)-α-carbamino-α-cyano-1-ylidene (3a) could be exploited as an excellent antibiofilm agent against carbapenem-resistant E. coli bacteria strains.     

Photodynamic inactivation of multiresistant bacteria (KPC) using zinc(II)phthalocyanines

The worldwide increase in antibiotic resistance has led to search of alternatives anti-microbial therapies such as photodynamic inactivation. The aim of this paper was to evaluate the photodynamic activity in vitro of a neutral and two cationic Zn phthalocyanines. Their photokilling activity was tested on Escherichia coli ATCC 25922 and Klebsiella pneumoniae Carbapenemase (KPC)-producing. After treating bacteria with phthalocyanines, the cultures were irradiated with white light. As a result, the bacteria were inactivated in presence of cationic phthalocyanines. The photoinactivation was dependent of the irradiation time and phthalocyanine concentration. The most effective photosensitizer on KPC-producing was Zinc(II)tetramethyltetrapyridino[2,3-b:2′,3′-g:2″,3″-l:2?,3?-q]porphyrazinium methylsulfate (ZnTM2,3PyPz). After irradiation using the water soluble ZnTM2,3PyPz (3 μM) the viability of KPC (30 min of irradiation) and E. coli (10 min of irradiation) decreased ≈99.995%.     

Antibacterial potential of Malaysian ethnomedicinal plants against methicillin-susceptible Staphylococcus aureus (MSSA) and methicillin-resistant Staphylococcus aureus (MRSA)

This study aimed to evaluate the antibacterial activities of 61 plant extracts from 49 Malaysian ethnomedicinal plants and to investigate the interaction of the active plant extracts in combination with synthetic antibiotics against the MSSA and MRSA strains. The minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) of the plant extracts were determined using a microdilution method against MSSA and MRSA strains. The interaction between active plant extracts and the antibiotics was assessed using the checkerboard method. The total fractional inhibitory concentration (∑FIC) indices from the combination were calculated to determine the nature of the interaction. Out of the 61 plant extracts tested against the MSSA strain, 7 plant extracts (̴ 11%) showed MIC values of less than 200 μg/mL, 17 extracts (̴ 28%) showed MIC between 200 and 800 µg/mL and seed extracts of Areca catechu showed MBC values of 400 μg/mL. The seed extract of A. catechu showed MIC and MBC of 400 μg/mL against the MRSA strains while leaf extract of Cocos nucifera showed MIC of 400 μg/mL against MRSA NCTC 12493. When the active plant extracts (MIC ≤ 200 µg/mL for MSSA, and ≤ 400 µg/mL for MRSA) were tested in combination with vancomycin and ciprofloxacin, they showed no interaction against both MSSA and MRSA with ∑FIC between 1.06 and 2.03. These findings provide a preliminary overview of the anti-MSSA and anti-MRSA properties of Malaysian ethnobotanical plants to combat Staphylococcal infections. Further research is needed to establish an antibacterial profile of the tested plant extracts.     

Novel 5-methyl-2-phenylphenanthridium derivatives as FtsZ-targeting antibacterial agents from structural simplification of natural product sanguinarine

A novel series of 5-methyl-2-phenylphenanthridium derivatives were displayed outstanding activity against a panel of antibiotic-sensitive and -resistant bacteria strains compared with their precursor sanguinarine, ciprofloxacin and oxacillin sodium. Compounds 7?l, 7m and 7n were found to display the most effective activity against five sensitive strains (0.06–2?μg/mL) and three resistant strains (0.25–4?μg/mL). The kinetic profiles indicated that compound 7l possessed the strongest bactericidal effect on S. aureus ATCC25923, with the MBC value of 16?μg/mL. The cell morphology and the FtsZ polymerization assays indicated that these compounds inhibited the bacterial proliferation by interfering the function of bacterial FtsZ. The SARs showed that all the 4-methyl-substituted 5-methyl-2-phenylphenanthridium subseries could be further investigated as the FtsZ-targeting antibacterial agents.     

New β-lactam – Tetramic acid hybrids show promising antibacterial activities

β-Lactams are the most important class of antibiotics, for which the emergence of resistance threatens their utility. As such, we explored the extent to which the tetramic acid motif, frequently found in naturally occurring antibiotics, can be used to generate novel β-lactam antibiotics with improved antibacterial activity. We synthesized new ampicillin – tetramic acid, cephalosporin – tetramic acid, and cephamycin – tetramic acid analogs and evaluated their activities against problematic Gram-positive and Gram-negative pathogens. Amongst the analogs, a 7-aminocephalosporanic acid analog, 3397, and a 7-amino-3-vinyl cephalosporanic acid, 3436, showed potent activities against S. aureus NRS 70 (MRSA) with MICs of 6.25?μg/mL and 3.13?μg/mL respectively. These new analogs were ≥16-fold more potent than cefaclor and cephalexin. Additionally, a Δ² cephamycin – tetramic acid analog 3474 which contained a basic guanidinium substituent at the 5-position of the tetramic acid core displayed potent activity against several clinical strains of K. pneumoniae and E. coli.     

Two new alkaloids from Pachysandra terminalis and their antibacterial activity assessment

Phytochemical investigation of a 90 % ethanol extract of Pachysandra terminalis Sieb. Et Zucc led to the isolation of a novel alkaloid, terminamine T (1); a new pregnane-type alkaloid, terminamine U (2); and four known pregnane-type alkaloids (3-6). The structures of these compounds were elucidated on the basis of nuclear magnetic resonance spectra, mass spectrometry data, single-crystal X-ray diffraction, and by a comparison with data from the literature. All compounds were evaluated for their antibacterial activities against gram-positive (S. aureus, ATCC 29213) and gram-negative (E. coli, ATCC 25922) bacteria. Compounds 2-6 exhibited generally modest to poor antibiotic properties. Furthermore, compound 2 showed antibacterial activity against methicillin-resistant Staphylococcus epidermidis (MRSE), methicillin-resistant Staphylococcus aureus (MRSA), and methicillin-resistant Staphylococcus aureus USA300 (LAC) with a minimal inhibitory concentration (MIC) value of 32 μg/mL (75 μM) and minimum bactericidal concentration (MBC) values of 64, 128, and 128 μg/mL (150, 300, and 300 μM), respectively.     

Antibacterial activity of indolyl-quinolinium derivatives and study their mode of action

Filamenting temperature-sensitive mutant Z (FtsZ) is recognized as a promising target for new antibiotics development because of its high conservatism and pivotal role in the bacteria cell division. The aromatic heterocyclic scaffold of indole is known showing merit medical functions in antiviral and antimicrobial. In the present study, a series of 1-methylquinolinium derivatives, which were integrated with an indole fragment at its 2-position and a variety of amino groups (cyclic or linear, mono- or di-amine) at the 4-position were synthesized and their antibacterial activities were evaluated. The results of antibacterial study show that the representative compounds can effectively inhibit the growth of testing strains including MRSA and VRE, with MIC values of 1–4?μg/mL by bactericidal mode. The mode of action assays revealed that c2 can effectively disrupt the rate of GTP hydrolysis and dynamic polymerization of FtsZ, and thus inhibits bacterial cell division and then causes bacterial cell death. In addition, the result of resistance generation experiment reveals that c2 is not likely to induce resistance in S. aureus.     

Additive effect of heparin on the photoinactivation of Escherichia coli using tricationic P-porphyrins

Polycationic porphyrins have received substantial attention in developing singlet oxygen-sensitizers for biological use such as in the photoinactivation of bacteria and photodynamic therapy (PDT) of tumor cells because they have strong binding affinities for DNA and proteins. However, these strong cellular interactions can retard elimination of the drug after PDT. Therefore, the studies on the interactions of porphyrins with other molecules present much interest, in order to modulate the sensitizers’ activity or even remove them from the human body after PDT. Here, we studied the additive effect of heparin on the photoinactivation by polycationic porphyrins using Escherichia coli as a model cell. Tricationic P-porphyrin sensitizers substituted with an N-alkylpyridinium group (alkyl?=?pentyl (1a), hexyl (1b), and heptyl (1c)) or N-hexylammonium (1d) as the axial ligand were used. Additionally, dicationic Sb-porphyrin substituted with an N-hexylpyridinium group (1e) was prepared. We studied the additive effect of heparin on the photoinactivation of E. coli by 1a–1e. The bactericidal activities were evaluated using the half-life (T_1/2 in min) of E. coli and the minimum effective concentrations ([P]) of the porphyrin sensitizers. In the absence of heparin, the [P] values were determined to be 0.4–0.5?μM for 1a?1c and 2.0?μM for 1d?1e. The bactericidal activity of 1a?1c was completely retarded by the addition of heparin (1.0?μM). However, the addition of heparin (1.0?μM) could not completely retard the bactericidal activity of 1d?1e whose [P] values were relatively large. It is suggested that tricationic 1a?1c adsorbed onto the anionic heparin through electrostatic interactions. The adsorption of 1 on heparin disturbs the uptake of 1 into E. coli cells. Thus, the addition of heparin was found to be a useful method for retarding photoinactivation.     

Design and synthesis of biaryloxazolidinone derivatives containing a rhodanine or thiohydantoin moiety as novel antibacterial agents against Gram-positive bacteria

Novel biaryloxazolidinone derivatives containing a rhodanine or thiohydantoin moiety were designed, synthesized and evaluated for their antibacterial activity. The key compounds 7 and 9 were synthesized by the knoevenagel condensation of intermediate aldehyde 5 with rhodanine derivatives 6a?6b. The preliminary study showed that compounds 7, 9 and 10e exhibited potent antibacterial activity with MIC values of 0.125?µg/mL against S. aureus, MRSA, MSSA, LREF and VRE pathogens, using linezolid and radezolid as the positive controls. The most promising compound 10e exhibited potent antibacterial activity against tested clinical isolates of MRSA, MSSA, VRE and LREF with MIC values in the range of 0.125–0.5?µg/mL, and the potency of 10e against clinical isolates of LREF was 64-fold higher than that of linezolid. Moreover, compound 10e was non-cytotoxic with an IC₅₀ value of 91.04?μM against HepG2 cell. Together, compound 10e might serve as a novel antibacterial agent for further investigation.     

Synthesis and evaluation of novel sulfenamides as novel anti Methicillin-resistant Staphylococcus aureus agents

A total of 29 novel sulfenamide compounds were synthesized, spectroscopically characterized and evaluated in vitro for antimicrobial activity against various infectious pathogens. Compounds 1b and 2c exhibited potent inhibition against clinical Methicillin-resistant Staphylococcus aureus (MRSA) strains with minimum inhibitory concentration (MIC) values of 1.56 μg/mL.     

Synthesis and biological evaluation of rhodanine derivatives bearing a quinoline moiety as potent antimicrobial agents

Three series of rhodanine derivatives bearing a quinoline moiety (6a–h, 7a–g, and 8a–e) have been synthesized, characterized, and evaluated as antibacterial agents. The majority of these compounds showed potent antibacterial activities against several different strains of Gram-positive bacteria, including multidrug-resistant clinical isolates. Of the compounds tested, 6g and 8c were identified as the most effective with minimum inhibitory concentration (MIC) values of 1 μg/mL against multidrug-resistant Gram-positive organisms, including methicillin-resistant and quinolone-resistant Staphylococcus aureus (MRSA and QRSA, respectively). None of the compounds exhibited any activity against the Gram-negative bacteria Escherichia coli 1356 at 64 μg/mL. The cytotoxic activity assay showed that compounds 6g, 7g and 8e exhibited in vitro antibacterial activity at non-cytotoxic concentrations. Thus, these studies suggest that rhodanine derivatives bearing a quinoline moiety are interesting scaffolds for the development of novel Gram-positive antibacterial agents.     

Synthesis,biological evaluations and computational studies of N-(3-(-2-(7-Chloroquinolin-2-yl)vinyl) benzylidene)anilines as fungal biofilm inhibitors

In the present investigation, new chloroquinoline derivatives bearing vinyl benzylidene aniline substituents at 2nd position were synthesized and screed for biofilm inhibitory, antifungal and antibacterial activity. The result of biofilm inhibition of C. albicans suggested that compounds 5j (IC₅₀ value?=?51.2?μM) and 5a (IC₅₀ value?=?66.2?μM) possess promising antibiofilm inhibition when compared with the standard antifungal drug fluconazole (IC₅₀?=?40.0?μM). Two compounds 5a (MIC?=?94.2?μg/mL) and 5f (MIC?=?98.8?μg/mL) also exhibited good antifungal activity comparable to standard drug fluconazole (MIC?=?50.0?μg/mL). The antibacterial screening against four strains of bacteria viz. E. coli, P. aeruginosa, B. subtilis, and S. aureus suggested their potential antibacterial activity and especially all the compounds except 5g were found more active than the standard drug ciprofloxacin against B. subtilis. To further gain insights into the possible mechanism of these compounds in biofilm inhibition through the agglutinin like protein (Als), molecular docking and molecular dynamics simulation studies were carried out. Molecular modeling studies suggested the clear role in inhibition of this protein and the resulting biofilm inhibitory activity.     

Synthesis and in vitro antibacterial activity of novel fluoroquinolone derivatives containing substituted piperidines

We report herein the synthesis of novel 7-(4-alkoxyimino-3-aminomethyl-3-methylpiperidin-1-yl) fluoroquinolone derivatives. The antibacterial activity of the newly synthesized compounds was evaluated and correlated with their physicochemical properties. Results reveal that all of the target compounds have good potency in inhibiting the growth of Staphylococcus aureus and Staphylococcus epidermidis including MRSE (MIC: 0.125–4 μg/mL). Compounds 12, 13 are more potent than or comparable to levofloxacin against MRSA, Streptococcus pyogenes, Escherichia coli, Klebsiella pneumoniae, and Shigella sonnei. Compound 17 is more active than or comparable to levofloxacin against S. aureus including MRSA, S. epidermidis and S. pyogenes.     

Blepharismin produced by a protozoan Blepharisma functions as an antibiotic effective against methicillin-resistant Staphylococcus aureus

A ciliated protozoan, Blepharisma japonicum, produces a photosensitive red pigment, blepharismin (BLR). This study showed that the pigment inhibits the growth of Gram-positive bacteria, such as methicillin-resistant Staphylococcus aureus (MRSA) resistant to arbekacin (ABK), which is the most effective aminoglycoside antibiotic against MRSA and used world wide. Although the minimum inhibitory concentration (MIC) of BLR to the ABK-resistant MRSA strain was 6.25 μg/ml in dark, it was decreased to 1.25 μg/ml by irradiation with white light of 65 W/m² for 30 min, suggesting that the antibacterial activity of BLR is photoactivated. Our findings suggested that the antibacterial activity of BLR in dark is due to inhibition of protein synthesis. In addition, we found that BLR is bactericidal and enhances synergistically the antibacterial activity of ABK.     

Aspernolides F and G,new butyrolactones from the endophytic fungus Aspergillus terreus

Two new butyrolactones: aspernolides F (6) and G (7), together with three stigmasterol derivatives: (22E,24R)-stigmasta-5,7,22-trien-3-β-ol (1), stigmast-4-ene-3-one (2), and stigmasta-4,6,8(14), 22-tetraen-3-one (3), two meroterpenoids: terretonin A (4) and terretonin (5), and a butyrolactone derivative: butyrolactone VI (8) have been isolated from the endophytic fungus Aspergillus terreus isolated from the roots of Carthamus lanatus (Asteraceae). Their structures were determined by spectroscopic means (1D, 2D NMR, and HRESIMS), as well as optical rotation measurement and comparison with literature data. The isolated compounds were evaluated for their anti-microbial, anti-malarial, anti-leishmanial, and cytotoxic activities. Compound 1 displayed a potent activity against MRSA and C. neoformans with IC₅₀ values of 0.96 μg/mL and 4.38 μg/mL, respectively compared to ciprofloxacin (IC₅₀ 0.07 μg/mL) and amphotericin B (IC₅₀ 0.34 μg/mL), respectively. While, 6 showed good activity against C. neoformans (IC₅₀ 5.19 μg/mL) and mild activity against MRSA (IC₅₀ 6.39 μg/mL). Moreover, 1 and 2 exhibited very good anti-leishmanial activity towards L. donovani with IC₅₀ values of 4.61 and 6.31 μg/mL, respectively and IC₉₀ values of 6.02 and 16.71 μg/mL, respectively.     

Design,synthesis, neuroprotective,antibacterial activities and docking studies of novel thieno[2,3-d]pyrimidine-alkyne Mannich base and oxadiazole hybrids

A series of thieno[2,3-d]pyrimidine alkyne Mannich base derivatives (7a-e, 8a-e) and thieno[2,3-d]pyrimidine 1,3,4-oxadiazole derivatives (9a-e, 10a-e) have been synthesized and evaluated for their neuroprotective and neurotoxicity activities where 9a, 10d displayed good neuroprotection 10.6 and 11.88?µg/mL respectively against the H₂O₂ induced cell death at the EC₅₀ values and 9b, 9d showed respective toxic effects on PC12 cells at CC₅₀ 86.12 and 94.16?µg/mL. Compounds 9a, 9e, 10a and 10b showed strong antibacterial activity against two gram positive (S. aureus, B. subtilis) and two gram-negative strains (E. coli, P. aeruginosa) and showed good binding affinities with C(30) carotenoid dehydrosqualene synthase, Gyrase A and LpxC. This is the first report for the demonstration of thieno[2,3-d] pyrimidine derivatives as promising neuroprotective agents against H₂O₂ induced neurotoxicity on PC12 cells.     

Design and synthesis of C10 modified and ring-truncated canthin-6-one analogues as effective membrane-active antibacterial agents

A series of canthin-6-one analogues were designed and synthesized in order to study their antibacterial activity and structure–activity relationships. Compound 22 showed a broad spectrum of antibacterial activity and exhibited better bactericidal effect (8-fold superiority against Staphylococcus aureus and 2-fold superiority against Ralstonia solanacearum) than fosfomycin sodium and propineb with a minimum inhibitory concentration value of 2?μg/mL. Moreover, it showed low cytotoxicity, stimulation on germination rates and good “drug-like” properties. Membrane-active mechanism was further studied by fluorescent microscopy, scanning electron microscopy, cytoplasmic β-galactosidase leakage assay and evaluation of the molecular docking. The results showed that 22 may exert its bactericidal effect by damaging bacterial cell membranes and influencing the membrane formation, both of which could lead to cell death. The in vivo antibacterial assay with a protective efficacy of 68% demonstrated the potential of C ring-truncated canthin-6-one 22 as a new bactericide.