Efficient synthesis and antimicrobial activity of some novel S-β-d-glucosides of 5-aryl-1,2,4-triazole-3-thiones derivatives

A series of 3-S-β-d-glucosides-4-arylideneamino-5-aryl-1,2,4-triazoles were rationally designed and synthesized according to the principle of superposition of bioactive substructures by the combination of 1,2,4-triazole, Schiff base and glucosides. The structures of the target compounds have been characterized by ¹H NMR, ¹³C NMR, IR, MS and HRMS. All the newly synthesized compounds have been evaluated for their antimicrobial activities in vitro against Staphylococcus aureus (ATCC 6538), Escherichia coli (ATCC 8099) as well as Monilia albican (ATCC 10231). The bioactive assay showed that most of the tested compounds displayed variable inhibitory effects on the growth of the Gram-positive bacterial strain (Staphylococcus aureus), Gram-negative bacterial strains (Escherichia coli) and fungal strains (Monilia albican). All the target compounds exhibited better antifungal activity than antibacterial activity. Especially, compounds 6b, 6c, 6f, 6j, 6k and 6l showed excellent activity against fungus Monilia albican with MIC values of 16 μg/mL.     

A novel series of 11-O-carbamoyl-3-O-descladinosyl clarithromycin derivatives bearing 1,2,3-triazole group: Design,synthesis and antibacterial evaluation

A series of novel 11-O-carbamoyl-3-O-descladinosyl clarithromycin derivatives bearing the 1,2,3-triazole group were designed, synthesized, and evaluated for their in vitro antibacterial activity. The antibacterial results indicated that most of the target compounds not only increased their activity against resistant bacterial strains, but also partially retained the activity against sensitive bacterial strains compared with clarithromycin. Among them, 13d had the best antibacterial activity against resistant strains, including Streptococcus pneumoniae B1 expressing the ermB gene (16 µg/mL), Streptococcus pneumoniae AB11 expressing the mefA and ermB genes (16 µg/mL) and Streptococcus pyogenes R1 (16 µg/mL), showing >16, 8 and 16-fold higher activity than that of CAM, respectively. Moreover, 13d and 13g exhibited the best antibacterial activity against sensitive bacterial strains, including Staphylococcus aureus ATCC25923 (4 µg/mL) and Bacillus Subtilis ATCC9372 (1 µg/mL). The MBC results showed that the most promising compounds 13d and 13g exhibited antibacterial activity through bacteriostatic mechanism, while the time-kill kinetic experiment revealed bactericidal kinetics of 13g from microscopic point of view. In vitro antibacterial experiments and molecular docking results further confirmed that it was feasible to our initial design strategy by modifying the C-3 and C-11 positions of clarithromycin to increase the activity against resistant bacteria.     

Antibacterial,tyrosinase, and DNA photocleavage studies of some triazolylnucleosides

In order to explore the biological potential, some synthesized triazolylnucleosides were evaluated for their antibacterial, tyrosinase and DNA photocleavage activities. Triazolylnucleosides (5–12) were screened against Staphylococcus aureus (ATCC 6538), gram-positive and Escherichia coli (ATCC 10536), gram-negative bacterial strains. Among the series, compound 9 exhibited a significant level of antibacterial activity against both strains at higher concentration in reference to the standard drug, Levofloxacin. Tyrosinase activity and inhibition of these compounds were also studied, and it has been found that compounds 8 and 11 displayed more than 50% inhibitory activity. In addition, six compounds (7–12) were evaluated for their DNA photocleavage activity. The compounds 8 and 12 exhibited excellent DNA photocleavage activity at a concentration of 10 μg and may be used as template for antitumor drugs in the future.     

Synthesis, crystal structures and in vitro antibacterial activity of two novel organotin(IV) complexes

Two triorganotin(IV) carboxylates [nBu₃SnOL]_n (KK1) and [Ph₃SnOL]_n (KK2) have been prepared by the reactions of (E)-3-(4-(diphenylamino)phenyl)acrylic acid (HL) with n(Bu₃Sn)₂O and Ph₃Sn(OH), respectively. Complexes KK1 and KK2 have been structurally characterized by IR, elemental analysis and X-ray crystallography, confirming that both complexes possess infinite 1D chain structures. It’s exciting to discover that KK1 and KK2 exhibit strong solid-state luminescence emission while the HL almost quenches. Furthermore, both complexes were assayed for in vitro antibacterial activity against two Gram-positive bacterial strains (Bacillus subtilis ATCC 6633 and Staphylococcus aureus ATCC 6538) and two Gram-negative bacterial strains (Pseudomonas aeruginosa ATCC 13525 and Escherichia coli ATCC 35218) by MTT method. Complex KK2 exhibited powerful antibacterial activities against S. aureus with MIC value of 0.78 μg/mL, which was superior to the positive controls penicillin G. On the basis of the biological results, structure-activity relationships were discussed.     

Two new sesquiterpene derivatives from soil actinomycete Streptomyces albospinus 15-4-2

Two new sesquiterpene derivatives, 4α,10β-dimethyl-decahydronaphthalene-1β,3β,5α,8α-tetraol (1) and 5β H-eudesmane-1β,6α,11-triol (2) were isolated from the soil actinomycete Streptomyces albospinus 15-4-2. Their structures were elucidated on the basis of spectroscopic analysis. Compound 1 exhibited antibacterial activity against methicillin-resistant Staphylococcus aureus (MRSA) strain in vitro.     

Synthesis and on-target antibacterial activity of novel 3-elongated arylalkoxybenzamide derivatives as inhibitors of the bacterial cell division protein FtsZ

Novel 3-elongated arylalkoxybenzamide derivatives were designed, synthesized and evaluated for their cell division inhibitory activity and antibacterial activity. Among them, the subseries of 3-alkyloxybenzamide derivatives exhibited greatly improved on-target activity against Bacillus subtilis and Staphylococcus aureus, and remarkably increased antibacterial activity against B. subtilis ATCC9372, penicillin-susceptible S. aureus ATCC25923, methicillin-resistant S. aureus ATCC29213 (MRSA) and penicillin-resistant S. aureus PR compared with 3-methoxybenzamide. In contrast, the subseries of 3-phenoxyaklyloxybenzamide, 3-heteroarylalkyloxybenzamide and 3-heteroarylthioalkyloxybenzamide derivatives only showed a significant improvement in on-target activity and antibacterial activity against B. subtilis ATCC9372.     

Synthesis and antibacterial evaluation of novel 11-O-aralkylcarbamoyl-3-O-descladinosylclarithromycin derivatives

A series of novel 11-O-aralkylcarbamoyl-3-O-descladinosylclarithromycin derivatives were designed, synthesized and evaluated for their in vitro antibacterial activity. The results showed that the majority of the target compounds displayed potent activity against erythromycin-susceptible S. pyogenes, erythromycin-resistant S. pneumoniae A22072 expressing the mef gene and S. pneumoniae AB11 expressing the mef and erm genes. Besides, most of the target compounds exhibited moderate activity against erythromycin-susceptible S. aureus ATCC25923 and B. subtilis ATCC9372. In particular, compounds 11a, 11b, 11c, 11e, 11f and 11h were found to exert favorable antibacterial activity against erythromycin-susceptible S. pyogenes with the MIC values of 0.015–0.125?μg/mL. Furthermore, compounds 10e, 11a, 11b and 11c showed superior activity against erythromycin-resistant S. pneumoniae A22072 with the MIC values of 0.25–0.5?μg/mL. Additionally, compound 11c was the most effective against all the erythromycin-resistant S. pneumoniae strains (A22072, B1 and AB11), exhibiting 8-, 8- and 32-fold more potent activity than clarithromycin, respectively.     

Novel depsides as potential anti-inflammatory agents with potent inhibitory activity against Escherichia coli-induced interleukin-8 production

Sixteen novel depsides were synthesized for the first time. Their chemical structures were clearly determined by ¹H NMR, ESI mass spectra, and elemental analyses. All the compounds were assayed for antibacterial activities against three Gram-positive bacterial strains (Bacillus subtilis ATCC 6633, Staphylococcus aureus ATCC 6538, and Streptococcus faecalis ATCC 9790) and three Gram-negative bacterial strains (Escherichia coli ATCC 35218, Pseudomonas aeruginosa ATCC 13525, and Enterobacter cloacae ATCC 13047) by the MTT method. Compound 2-(2-methoxy-2-oxoethyl)phenyl 5-bromonicotinate (5) exhibited significant antibacterial activities against E. coli ATCC 35218 with an MIC of 0.78 μg/mL, which was superior to the positive control kanamycin B. In addition, compound 5 showed potent inhibitory activity against E. coli-induced interleukin-8 production.     

Design,synthesis and antibacterial evaluation of honokiol derivatives

Staphylococcus aureus is a major and dangerous human pathogen that causes a range of clinical manifestations of varying severity, and is the most commonly isolated pathogen in the setting of skin and soft tissue infections, pneumonia, suppurative arthritis, endovascular infections, foreign-body associated infections, septicemia, osteomyelitis, and toxic shocksyndrome. Honokiol, a pharmacologically active natural compound derived from the bark of Magnolia officinalis, has antibacterial activity against Staphylococcus aureus which provides a great inspiration for the discovery of potential antibacterial agents. Herein, honokiol derivatives were designed, synthesized and evaluated for their antibacterial activity by determining the minimum inhibitory concentration (MIC) against S. aureus ATCC25923 and Escherichia coli ATCC25922 in vitro. 7c exhibited better antibacterial activity than other derivatives and honokiol. The structure-activity relationships indicated piperidine ring with amino group is helpful to improve antibacterial activity. Further more, 7c showed broad spectrum antibacterial efficiency against various bacterial strains including eleven gram-positive and seven gram-negative species. Time-kill kinetics against S. aureus ATCC25923 in vitro revealed that 7c displayed a concentration-dependent effect and more rapid bactericidal kinetics better than linezolid and vancomycin with the same concentration. Gram staining assays of S. aureus ATCC25923 suggested that 7c could destroy the cell walls of bacteria at 1 × MIC and 4 × MIC.     

Serine-based surfactants as effective antimicrobial agents against multiresistant bacteria

The antimicrobial activity of two serine derived gemini cationic surfactants, amide (12Ser)₂CON12 and ester (12Ser)₂COO12, was tested using sensitive, E. coli ATCC 25922 and S. aureus ATCC 6538, and resistant, E. coli CTX M2, E. coli TEM CTX M9 and S. aureus ATCC 6538 and S. aureus MRSA ATCC 43300 Gram-positive and Gram-negative bacteria strains. Very low MIC values (5 μM) were found for the two resistant strains E.coli TEM CTX M9 and S. aureus MRSA ATCC 43300, in the case of the amide derivative, and for S. aureus MRSA ATCC 43300, in the case of the ester derivative. The interaction of the serine amphiphiles with lipid-model membranes (DPPG and DPPC) was investigated using Langmuir monolayers. A more pronounced effect on the DPPG than on the DPPC monolayer was observed. The effect induced by the surfactants on bacteria membrane was explored by Atomic Force Microscopy. A clear disruption of the bacteria membrane was observed for E. coli TEM CTX M9 upon treatment with (12ser)₂CON12, whereas for the S. aureus MRSA few observable changes in cell morphology were found after treatment with either of the two surfactants. The cytotoxicity of the two compounds was assessed by hemolysis assay on human red blood cells (RBC). The compounds were shown to be non-cytotoxic up to 10 μM. Overall, the results reveal a promising potential, in particular of the amide derivative, as antimicrobial agent for two strains of antibiotic resistant bacteria.     

Synthesis of amides from (E)-3-(1-chloro-3,4-dihydronaphthalen-2-yl)acrylic acid and substituted amino acid esters as NorA efflux pump inhibitors of Staphylococcus aureus

Inhibitors for NorA efflux pump of Staphylococcus aureus have attracted the attention of many researchers towards the discovery and development of novel efflux pump inhibitors (EPIs). In an attempt to find specific potent inhibitors of NorA efflux pump of S. aureus, a total of 15 amino acid conjugates of 3-(1-chloro-3,4-dihydronaphthalen-2-yl)acrylic acid (4–18) were synthesized using a simple convenient synthetic approach and bioevaluated against NorA efflux pump. Two compounds 7 and 8 (each having MEC of 1.56?µg/mL) were found to restore the activity of ciprofloxacin through reduction of the MIC elucidated by comparing the ethidium bromide efflux in dose dependent manner in addition to ethidium bromide efflux inhibition and accumulation study using NorA overexpressing strain SA-1199B. Most potent compounds among these were able to restore the antibacterial activity of ciprofloxacin completely against SA-1199B. Structure activity relationship (SAR) studies and docking study of potent compounds 7 and 8 could elucidate the structural requirements necessary for interaction with the NorA efflux pumps. On the whole, compounds 7 and 8 have ability to reverse the NorA efflux mediated resistance and could be further optimized for development of potent efflux pump inhibitors.     

Discovery and initial structure–activity relationships of N-benzyl tricyclic indolines as antibacterials for methicillin-resistant Staphylococcus aureus

Methicillin-resistant Staphylococcus aureus (MRSA) is one of the most prevalent drug resistant bacteria. In 2012, over 11,000 fatalities in the United States were directly attributable to MRSA. In an effort to develop novel structural and mechanistic classes of antibacterial agents to fight against MRSA, we have optimized a hit compound, Of4, previously discovered in a screening campaign of a bio-inspired polycyclic indoline library previously developed in our lab. We took advantage of our concise and versatile synthetic strategy to conduct initial structure–activity relationship studies of Of4, and we now report the discovery of compound 4k as a more potent antibacterial agent against S. aureus. Compound 4k also displayed equivalent activity in four MRSA and a methicillin-susceptible strains while demonstrating an improved mammalian cytotoxicity profile compared to Of4. Interestingly, 4k shares the same tricyclic indoline core as Of1, a β-lactam-selective resistance-modifying agent, but harbors a distinct modification pattern conferring unique bioactivity. This phenomenon is reminiscent of many bioactive natural products.     

The Antibacterial Properties of 4, 8, 4′, 8′-Tetramethoxy (1,1′-biphenanthrene) -2,7,2′,7′-Tetrol from Fibrous Roots of Bletilla striata

Biphenanthrene compound, 4, 8, 4′, 8′-tetramethoxy (1, 1′-biphenanthrene)—2, 7, 2′, 7′-tetrol (LF05), recently isolated from fibrous roots of Bletilla striata, exhibits antibacterial activity against several Gram-positive bacteria. In this study, we investigated the antibacterial properties, potential mode of action and cytotoxicity. Minimum inhibitory concentrations (MICs) tests showed LF05 was active against all tested Gram-positive strains, including methicillin-resistant Staphylococcus aureus (MRSA) and staphylococcal clinical isolates. Minimum bactericidal concentration (MBC) tests demonstrated LF05 was bactericidal against S. aureus ATCC 29213 and Bacillus subtilis 168 whereas bacteriostatic against S. aureus ATCC 43300, WX 0002, and other strains of S. aureus. Time-kill assays further confirmed these observations. The flow cytometric assay indicated that LF05 damaged the cell membrane of S. aureus ATCC 29213 and B. subtilis 168. Consistent with this finding, 4 × MIC of LF05 caused release of ATP in B. subtilis 168 within 10 min. Checkerboard test demonstrated LF05 exhibited additive effect when combined with vancomycin, erythromycin and berberine. The addition of rat plasma or bovine serum albumin to bacterial cultures caused significantly loss in antibacterial activity of LF05. Interestingly, LF05 was highly toxic to several tumor cells. Results of these studies indicate that LF05 is bactericidal against some Gram-positive bacteria and acts as a membrane structure disruptor. The application of biphenanthrene in the treatment of S. aureus infection, especially local infection, deserves further study.     

Design,synthesis and molecular modeling studies of new series of s-triazine derivatives as antimicrobial agents against multi-drug resistant clinical isolates

Three novel series of s-triazine derivatives, including thirty-five new compounds 2a-d, 3a-3p, 4b-d, 5b-d, 6d-6d, and 7a-7f were synthesized comprising a diversity of substituents based on the structure of Astrazeneca arylaminotriazine DNA gyrase B inhibitor. The antimicrobial activity was determined for all compounds against Staphylococcus aureus, Escherichia coli and Candida albicans using the two-fold serial dilution technique and against reference standards Ampicillin for the antibacterial screening and Clotrimazole regarding the antifungal evaluation. The tested compounds showed strong to moderate antibacterial inhibitory action and weak antifungal activity. Compounds 3j and 6b were the most potent antibacterial agents against the tested strains and multi-drug resistant (MDR) clinical isolates of Klebsiella pneumoniae and methicillin resistant Staphylococcus aureus (MRSA1) with minimal toxicity in comparison to the reference drugs. In silico molecular properties calculations and molecular docking study for 3j and 6b revealed that both compounds could be considered as promising antibacterial DNA gyrase B inhibitors.     

Synthesis,molecular docking and biological evaluation of metronidazole derivatives containing piperazine skeleton as potential antibacterial agents

Metronidazole has a broad-spectrum antibacterial activity. Hereby a series of novel metronidazole derivatives were designed and synthesized based on nitroimidazole scaffold in order to find some more potent antibacterial drugs. For these compounds which were reported for the first time, their antibacterial activities against Escherichia coli, Pseudomonas aeruginosa, Bacillus subtilis and Staphylococcus aureus were tested. These compounds showed good antibacterial activities against Gram-positive strains. Compound 4m represented the most potent antibacterial activity against S. aureus ATCC 25923 with MIC of 0.003 μg/mL and it showed the most potent activity against S. aureus TyrRS with IC₅₀ of 0.0024 μM. Molecular docking of 4m into S. aureus tyrosyl-tRNA synthetase active site were also performed to determine the probable binding mode.     

Anthraquinone derivatives from the mangrove-derived fungus Phomopsis sp. PSU-MA214

One new tetrahydroanthraquinone derivative, (2R,3S)-7-ethyl-1,2,3,4-tetrahydro-2,3,8-trihydroxy-6-methoxy-3-methyl-9,10-anthracenedione (1), together with five known anthraquinones (2–6), two known phenylethyl alcohols (7–8) and one known butanamide (9), were isolated from the mangrove-derived fungus Phomopsis sp. PSU-MA214. Their structures were established by spectroscopic evidence. Compound 1 is a rare ethyltetrahydroanthraquinone and exhibited weak cytotoxicity against breast cancer (MCF-7) cell lines and antibacterial activity against the standard Staphylococcus aureus ATCC25923 and methicillin-resistant S. aureus SK1.     

Design and synthesis of biaryloxazolidinone derivatives containing amide or acrylamide moiety as novel antibacterial agents against Gram-positive bacteria

A series of novel biaryloxazolidinone derivatives containing amide and acrylamide structure were designed, synthesized and evaluated for their antibacterial activity. Most compounds generally exhibited potent antibacterial activity with MIC values of 1 μg/mL against S. aureus, MRSA, MSSA, LREF and VRE pathogens, using linezolid and radezolid as positive controls. Compound 17 exhibited good antibacterial activity with MIC values of 0.5 μg/mL against S. aureus, MRSA, MSSA and VRE and 0.25 μg/mL against LREF. The results indicated that compound 17 might serve as a potential hit-compound for further investigation.     

Bioactive cytosporone derivatives isolated from the mangrove-derived fungus Dothiorella sp. ML002

Three new cytosporone derivatives dothiorelones K–M (1, 2 and 7), together with six known ones (3–6, 8 and 9) were isolated from the mangrove-derived fungus Dothiorella sp. ML002. Their structures were determined by comprehensive 1D, 2D NMR spectroscopic and HR-ESI-MS spectroscopic data. Compounds 1, 2 and 5 displayed inhibitory activities against α-glucosidase with the IC₅₀ values of 22.0, 77.9 and 5.4 μg/mL, respectively. Additionally, compounds 1, 2, and 5 also exhibited antibacterial activities against Staphylococcus aureus (ATCC 6538) with the same MIC values of 50 μg/mL, respectively. The results indicated that cytosporone derivatives will be useful to as diabetes control agents.     

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.     

A concise synthesis and antimicrobial activities of 3-polyamino-23,24-bisnorcholanes as steroid-polyamine conjugates

A series of steroid-polyamine conjugates were synthesized and evaluated for their antimicrobial activity. This study was focused on the effect of stereochemistry at the C-3 and C-5 of steroids and types of polyamine at C-3 on activity against various human pathogens. All the conjugates exhibited strong antimicrobial activities against Gram-positive strains. Compound 18 was found to be the most potent in these series with a MIC value as low as 1 μg/mL against the bacterium Staphylococcus aureus ATCC6538P.