Synthesis and antibacterial studies of binaphthyl-based tripeptoids. Part 1

An efficient synthesis of 29 new binaphthyl-based neutral, and mono- and di-cationic, peptoids is described. Some of these compounds had antibacterial activities with MIC values of 1.9–3.9 μg/mL against Staphylococcus aureus. One peptoid had a MIC value of 6 μg/mL against a methicillin-resistant strain of S. aureus (MRSA) and a MIC value of 2 μg/mL against vancomycin-resistant strains of enterococci (VRE).     

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.     

3-Aryl-4-acyloxyethoxyfuran-2(5H)-ones as inhibitors of tyrosyl-tRNA synthetase: Synthesis,molecular docking and antibacterial evaluation

Thirty-eight 3-aryl-4-acyloxyethoxyfuran-2(5H)-ones were designed, prepared and tested for antibacterial activities. Some of them showed significant antibacterial activity against Gram-positive organism, Gram-negative organism and fungus. Out of these compounds, 4-(2-(3-chlorophenylformyloxy)ethoxy)-3-(4-chlorophenyl)furan-2(5H)-one (d40) showed the widest spectrum of activity with MIC₅₀ of 2.0 μg/mL against Staphylococcus aureus, 4.3 μg/mL against Escherichia coli, 1.5 μg/mL against Pseudomonas aeruginosa and 1.2 μg/mL against Candida albicans. Our data disclosed that MIC₅₀ values against whole cell bacteria are positive correlation with MIC₅₀ values against tyrosyl-tRNA synthetase. Meanwhile, molecular docking of d40 into S. aureus tyrosyl-tRNA synthetase active site was also performed, and the inhibitor tightly fitting the active site might be an important reason why it has high antimicrobial activity.     

Design,synthesis and biological activity evaluation of novel 2,6-difluorobenzamide derivatives through FtsZ inhibition

Novel series of 3-substituted 2,6-difluorobenzamide derivatives as FtsZ inhibitors were designed, synthesized and evaluated for their in vitro antibacterial activity against various phenotype of Gram-positive and Gram-negative bacteria, and their cell division inhibitory activity against three representative strains. As a result, 3-chloroalkoxy derivative 7, 3-bromoalkoxy derivative 12 and 3-alkyloxy derivative 17 were found to exhibit the best antibacterial activity against Bacillus subtilis with MICs of 0.25–1 μg/mL, and good activity (MIC < 10 μg/mL) against both susceptible and resistant Staphylococcus aureus. Additionally, all the three compounds displayed potent cell division inhibitory activity with MIC values of below 1 μg/mL against Bacillus subtilis and Staphylococcus aureus.     

Cytosporone derivatives from the endophytic fungus Phomopsis sp. PSU-H188

Two new cytosporone derivatives (1 and 2) were isolated from the endophytic fungus Phomopsis sp. PSU-H188 together with 19 known compounds. Their structures were elucidated by analysis of spectroscopic data. Known mycoepoxydiene showed potent cytotoxic activity towards both MCF-7 and noncancerous Vero cell lines with the respective IC₅₀ values of 9.27 and 4.06 μM. It exhibited inhibition on glucose output in mouse primary hepatocytes with the IC₅₀ value of 16.06 μM, but did not show cytotoxicity on primary mouse hepatocytes. Additionally, known cytosporone B displayed protective activity against INS-1 832/13 pancreatic β-cells by an EC₅₀ value of 11.08 μM whereas known diaporthalasin displayed antibacterial activity against methicillin-resistant Staphylococcus aureus with an MIC value of 4 μg/mL. Both of them were noncytotoxic to Vero cells.     

Synthesis of fluorinated carbazoles via C–H arylation catalyzed by Pd/Cu bimetal system and their antibacterial activities

An effective intramolecular C–H arylation reaction catalyzed by a bimetallic catalytic system Pd(OAc)₂/CuI for the synthesis of fluorine-substituted carbazoles from corresponding N-phenyl-2-haloaniline derivatives under ligand free conditions is demonstrated. The established method is effective for both N-phenyl-2-bromoaniline and N-phenyl-2-chloroaniline, and requires the low loading of Pd(OAc)₂ (0.5 mol %). A series of new fluorinated carbazoles were synthesized in excellent yields using the protocol (>83%, 19 examples) and were fully characterized by ¹H, ¹³C and ¹⁹F NMR spectral data, HRMS and elemental analysis. All compounds were evaluated for their antibacterial activities against four bacteria (Bacillus subtilis, Staphylococcus aureus, Escherichia coli and methicillin-resistant S. aureus with resistance to gentamicin) by serial dilution technique. All tested compounds showed antibacterial activity against three test strains (S. aureus, B. subtilis and MRSA), and most of these compounds displayed pronounced antimicrobial activities against these three strains with low MIC values ranging from 0.39 to 6.25 μg/mL. Among them, compounds 7 and 14 exhibited potent inhibitory activity better than reference drugs meropenem and streptomycin. Three compounds (2, 4 and 5) showed antibacterial activity against E. coli. with MIC values from 12.5 to 25 μg/mL.     

Synthesis and biological evaluation of 5-aryloxypyrazole derivatives bearing a rhodanine-3-aromatic acid as potential antimicrobial agents

Three novel series of 5-aryloxypyrazole derivatives have been synthesized and tested for their antibacterial activity. The majority of the synthesized compounds showed potent inhibitory activity against Gram-positive bacteria Staphylococcus aureus 4220, especially against the strains of multidrug-resistant clinical isolates (MRSA3167/3506 and QRSA3505/3519). Among which compounds IIIb, IIIg and IIIm showed the most potent levels of activity (MIC = 1 μg/mL) against the multidrug-resistant strains. And cytotoxic activity assay showed that the compounds tested did not affect cell viability on the Human cervical (HeLa) cells at their MICs. The current study therefore suggests that 5-aryloxypyrazoles bearing a rhodanine-3-aromatic acid moiety are promising scaffolds for the development of novel Gram-positive antibacterial agents.     

Lemairones A and B: Two new antibacterial tetraflavonoids from the leaves of Zanthoxylum lemairei (Rutaceae)

Zanthoxylum lemairei is widely used in African folk medicine for its pharmacological relevance. Chemical investigation of the ethanol extract from the leaves of this plant lead to the isolation of two new tetraflavonoids, lemairones A (1) and B (2), along with three known compounds, lupeol, sitosterol, and sitosterol 3-O-β-d-glucopyranoside. The antibacterial screening of the leaves of this plant, characterization of compounds 1 and 2, and their antibacterial activity are reported for the first time. The isolation of the compounds was performed using different chromatographic methods while their structures were elucidated by spectroscopic techniques including MS and NMR, and by comparison of data with those of similar flavonoids reported in the literature. The isolated compounds and the crude extract were tested against ten Gram negative multi-resistance bacterial strains including clinical isolates using a broth dilution method. The crude ethanol extract showed weak activity against the tested bacteria strains with a minimal inhibitory concentration (MIC) ranging from 512 to 1024 μg/mL. Among the isolated metabolites, only the new tetraflavonoids were tested. Lemairone A displayed weak activity while lemairone B had moderate activity against the resistant Escherichia coli AG100 with MIC values of 128 μg/mL and 64 μg/mL respectively. In addition, both molecules displayed weak activity against Klebsiella pneumoniae KP55 (MIC 128 μg/mL).     

Phytochemical composition and biological activities of Asteriscus graveolens (Forssk) extracts

In the present study the phytochemical composition and biological activities of the aerial part extracts of Asteriscus graveolens against pathogenic bacteria and leishmania parasite were evaluated. Phytochemical analysis revealed the presence of polyphenols, flavonoids and tannins. The ethyl acetate fraction exhibited high antioxidant potential of 359.72 ± 32.03 μg and 326.76 ± 15.86 μg of ascorbic acid equivalents and 13.32 ± 0.19 μg/mL by PM, FRAP and DPPH assays respectively. This fraction also displayed a moderate antibacterial activity against Listeria monocytogenes ATCC 19115 (MIC = 0.312 mg/mL) and strong antileishmanial activity against both promastigote and amastigote forms with IC50 ranging from 22.93 ± 0.39 μg/mL to 35.23 ± 0.62 μg/mL. Furthermore the ethyl acetate fraction exhibited low cytotoxicity and good selectivity index towards the macrophage cell line Raw 264.7. HPLC analysis of the active fraction revealed the presence of hydroxycinnamic acid as major compound (30.56%). Asteriscus graveolens is a promising source of bioactive compounds that could be potentially used in cosmetic and pharmaceutical industry.     

Synthesis of novel 4-nitropyrrole-based semicarbazide and thiosemicarbazide hybrids with antimicrobial and anti-tubercular activity

We report the synthesis and screening of forty novel 4-nitropyrrole-semicarbazide conjugates inspired from the reported bio-potential of bromopyrrole alkaloids and semicarbazide derivatives for antimicrobial activity. Herein, hybrids 5k–5o, 5r, 5s and 5t displayed four-fold increased activity (MIC = 0.39 μg/mL) against Escherichia coli compared to standard ciprofloxacin. Eight hybrids, 5k–5o and 5r–5t displayed equal antibacterial activity (MIC = 1.56 μg/mL) against Klebsiella pneumonia compared to standard ciprofloxacin. Hybrid, 5k–5o (MIC = 0.195 μg/mL) displayed highly potent antibacterial activity against MSSA as compared to standard ciprofloxacin. Eight-fold superior activity was observed for four hybrids 5k–5m and 5o (MIC = 0.39 μg/mL) against MRSA. Further, nine hybrids displayed four-fold superior antifungal activity (MIC = 0.78 μg/mL) compared to standard Amphotericin B. Encouraging MICs of these hybrids recognize them as promising leads for development of potential antimicrobial drugs.     

2β-Acetoxyferruginol—A new antibacterial abietane diterpene from the bark of Prumnopitys andina

As part of an on-going project to isolate antibacterial compounds from rare conifer species, a new abietane diterpene, 2β-acetoxyferruginol was isolated from the stem bark of Prumnopitys andina. Molecular modelling studies were conducted to explain some of the NOEs observed in the A-ring of this compound and to support assignment of relative stereochemistry. This new compound had antibacterial activity at 8 μg/ml against two effluxing strains of Staphylococcus aureus, but interestingly was inactive at 128 μg/ml against a wild-type strain and against a methicillin-resistant (MRSA) clinical isolate. We have previously demonstrated that ferruginol is active against these four S. aureus stains and therefore the results indicate that the presence of the acetoxy group has a detrimental effect on antibacterial activity against certain strains. 2β-Acetoxyferruginol was also assayed against Propionibacterium acnes and was active at 4 μg/ml.     

Acylphloroglucinols from the fruits of Callistemon viminalis

Five new acylphloroglucinols, callistenones L-P (1–5), and three known compounds watsonianone A, callistenones F and H were isolated from the fruits of Callistemon viminalis. Callistenones L and M possessed a bisfuran fused-ring skeleton. Compounds 3–5 were acylphloroglucinol condensed with a β-triketone moiety via a pyrane. Their structures were established from analyses of NMR spectra, CD spectra and X-ray crystallography. Compound 8 showed antibacterial activity against S. aureus with MIC value of 20.3 μg/mL and E. coli with MIC value of 15.6 μg/mL.     

Synthesis and biological evaluation of pyrimidine analogs of antimycobacterial purines

Pyrimidine analogs of antimycobacterial 6-aryl-9-benzylpurines have been synthesized and screened for antibacterial activity against Mycobacterium tuberculosis H₃₇Rv in vitro. Several active compounds were identified and the best results were observed for 5-formamidopyrimidines. These compounds generally displayed IC₉₀ values ≤1 μg/mL, and they exhibited low toxicity towards mammalian cells. Imidazolylpyrimidines, which may be regarded as fleximer analogs of the parent purines, were also synthesized and one of them was found to be quite a potent inhibitor of M. tuberculosis (IC₉₀ 14 μg/mL).     

Benzimidazole-based antibacterial agents against Francisella tularensis

Francisella tularensis is a highly virulent pathogenic bacterium. In order to identify novel potential antibacterial agents against F. tularensis, libraries of trisubstituted benzimidazoles were screened against F. tularensis LVS strain. In a preliminary screening assay, remarkably, 23 of 2,5,6- and 2,5,7-trisubstituted benzimidazoles showed excellent activity exhibiting greater than 90% growth inhibition at 1 μg/mL. Among those hits, 21 compounds showed MIC₉₀ values in the range of 0.35–48.6 μg/mL after accurate MIC determination. In ex vivo efficacy assays, four of these compounds exhibited 2–3 log reduction in colony forming units (CFU) per mL at concentrations of 10 and 50 μg/mL.     

Bacterial Peptide deformylase inhibition of cyano substituted biaryl analogs: Synthesis,in vitro biological evaluation,molecular docking study and in silico ADME prediction

Herein, we report the synthesis and screening of cyano substituted biaryl analogs 5(a–m) as Peptide deformylase (PDF) enzyme inhibitors. The compounds 5a (IC₅₀ value = 13.16 μM), 5d (IC₅₀ value = 15.66 μM) and 5j (IC₅₀ value = 19.16 μM) had shown good PDF inhibition activity. The compounds 5a (MIC range = 11.00–15.83 μg/mL), 5b (MIC range = 23.75–28.50 μg/mL) and 5j (MIC range = 7.66–16.91 μg/mL) had also shown potent antibacterial activity when compared with ciprofloxacin (MIC range = 25–50 μg/mL). Thus, the active derivatives were not only potent PDF inhibitors but also efficient antibacterial agents. In order to gain more insight on the binding mode of the compounds with PDF, the synthesized compounds 5(a–m) were docked against PDF enzyme of Escherichia coli and compounds exhibited good binding properties. In silico ADME properties of synthesized compounds were also analyzed and showed potential to develop as good oral drug candidates.     

Design,synthesis and antibacterial activity studies of thiazole derivatives as potent ecKAS III inhibitors

Two series of thiazole derivatives containing amide skeleton were synthesized and developed as potent Escherichia coli β-ketoacyl-(acyl-carrier-protein) synthase III (ecKAS III) inhibitors. All the 24 new synthesized compounds were assayed for antibacterial activity against the respective Gram-negative and Gram-positive bacterial strains, including E. coli, Pseudomonas aeruginosa, Bacillus subtilis and Staphylococcus aureus. In which, 10 compounds with broad-spectrum antibacterial activities were further tested for their ecKAS III inhibitory activity. Last, we have successfully found that compound 4e showed both the promising broad antibacterial activity with MIC of 1.56–6.25 μg/mL against the representative bacterial stains, and also processed the most potent ecKAS III inhibitory activity with IC₅₀ of 5.3 μM. In addition, docking simulation also carried out in this study to give a potent prediction binding mode between the small molecule and ecKAS III (PDB code: 1hnj) protein.     

Synthesis of non-purine analogs of 6-aryl-9-benzylpurines,and their antimycobacterial activities. Compounds modified in the imidazole ring

Purine analogs modified in the five-membered ring have been synthesized and examined for antibacterial activity against Mycobacterium tuberculosis H₃₇Rv in vitro employing the microplate alamar blue assay (MABA). The 9-deaza analogs were only found to be weak inhibitors, but the 8-aza-, 7-deaza- and 8-aza-7-deazapurine analogs studied displayed excellent antimycobacterial activities, some even substantially better than the parent purine. In the 7-deazapurine series, MIC values between 0.08 and 0.35 μM, values comparable or better than the reference drugs used in the study (MIC rifampicin 0.09 μM, MIC isoniazid 0.28 μM and MIC PA-824 0.44 μM). The five most active compounds were also examined against a panel of drug-resistant Mtb strain, and they all retained their activity. The compounds examined were significantly less active against M. tuberculosis in a state of non-replicating persistence (NRP). MIC in the low-oxygen-recovery assay (LORA) ?60 μM. The 7-deazapurines were somewhat more toxic towards mammalian cells, but still the selectivity indexes were excellent. The non-purine analogs exhibit a selective antimycobacterial activity. They were essentially inactive against Staphylococcus aureus and Escherichia coli.     

A new δ-tocotrienolic acid derivative and other constituents from the cones of Cedrus atlantica and their in vitro antimicrobial activity

The phytochemical and antimicrobial properties of the cones of Cedrus atlantica (Endl) Manetti ex Carrière were investigated. Two new compounds (1,2) and nineteen known compounds (3–21) were isolated. Their structures were established by mass spectrometry (HRESIMS), 1D, 2D NMR and by comparison with literature data. Antimicrobial activity of hydromethanolic extract against a panel of 22 bacteria and yeasts showed an interesting antimicrobial activity. All compound purified from this extract were tested against S. aureus by bioautography. MIC values of the most active compounds were determined using a serial dilution technique. The results showed strong antibacterial activity of the abietane diterpenes 10, 11, 14, 15, 16 and 17. Dehydroabietic acid (17) was the most potent against Enterococcus faecalis (MIC = 15.1 = μg/mL), a multi-resistant commensal bacterium which can cause the fatal infections in humans.     

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.     

Chemical composition,angiotensin I-converting enzyme (ACE) inhibitory,antioxidant and antimicrobial activities of the essential oil from south Tunisian Ajuga pseudoiva Rob. Lamiaceae

The essential oil of Ajuga pseudoiva, collected from Tunisia, was analyzed using gas chromatography–mass spectroscopy. Thirty-two compounds accounting for 95.76% of the total oil were identified. Sesquiterpenes were found to be the most abundant components of A. pseudoiva oil. And they were mainly represented by viridiflorol (30.17%), germacrene B (9.26%) (α, β and γ)-eudesmol (8.11%) and aromadendrene (7.45%). The essential oil of A. pseudoiva showed radical scavengers activity (IC₅₀ = 0.72 mg/mL) and displayed lipid peroxidation inhibitory activity (IC₅₀ = 0.6 mg/mL). A. pseudoiva essential oil was also found to exhibit a dose-dependent ACE inhibitory activity with an IC₅₀ value of 65.5 μg/mL. Moreover, the antimicrobial activity of the essential oil was tested against 17 species of microorganisms, and the results obtained showed significant antibacterial activity against the Gram-positive and Gram-negative bacteria, with inhibition zones and minimal inhibitory concentration values of 14–32 mm and 84–137 μg/mL and 6–21 mm and 105–336 μg/mL, respectively. Higher activity was also found against several fungal strains.