Epileptogenic activity of some beta-lactam derivatives: structure-activity relationship

The epileptogenic activity of several derivatives of beta-lactam was compared following their intracerebroventricular administration in rats. At a dose of 0.033 mumol/kg cefazolin was the most powerful epileptogenic compound among the drugs tested; dramatic seizure signs (nodding, clonic convulsions and sometimes escape responses) were observed repeatedly. It was approximately three times more potent than benzylpenicillin and other similar compounds, such as ceftriaxone, cefoperazone and cefamandole. No epileptogenic signs were observed with equimolar doses of cefotaxime, cefonicid and ceftizoxime. All these derivatives differ from the substitution at position 3 and at position 7 of 7-aminocephalosporanic acid. The more convulsant compounds (i.e. cefazolin and ceftezole) are both derivatives of tetrazol and show a marked similarity with pentylentetrazol. In addition, aztreonam, a compound having only the beta-lactam ring substituted with a heterocyclic ring at the 4 position, possessed convulsant properties like those of cefoperazone and cefamandole. This suggests that the beta-lactam ring is able to produce epileptogenic activity and it seems likely that substitutions at the 7-aminocephalosporanic or 6-aminopenicillanic acid may increase or reduce the epileptogenic properties of beta-lactam derivatives.     

Some biological properties of cephalosporin c and a derivative

Some biological properties of cephalosporin C and of a pyridinium derivative, “cephalosporin C_A (pyridine),” were examined. Staphylococci, both penicillinase-producing and non-penicillinase-producing, and some other bacteria tested, were inhibited by 60 to 125 μg cephalosporin C/ml., and 5 to 20 μg cephalosporin C_A (pyridine)/ml. The ratio of the activity of the two antibiotics varied for different organisms. Resistance developed slowly on repeated subculture of penicillinase-producing staphylococci in presence of either antibiotic. The minimum inhibitory concentration of cephalosporin C_A (pyridine) upon penicillinase-producing staphylococci increased 4 to 8-fold with a 500-fold increase in inoculum size; with cephalosporin C there was a 2-fold increase. Their activity was not reduced by serum. Both substances were non-toxic. They were excreted quantitatively in the urine when given intravenously or subcutaneously to mice. After oral administration less than 5% of the dose was excreted. Cephalosporin C_A (pyridine) was about 8 times more active than cephalosporin C in protecting mice from an experimental streptococcal infection, nine doses of 6.25 mg/kg affording complete protection.     

New fluoroquinolone compounds with endo‐nortropine derivatives at C‐7 position show antibacterial activity against fluoroquinolone‐resistant strains of Staphylococcus aureus

A series of new fluoroquinolone analogs ( 3 – 18) were prepared, in three steps, by substituting chloro esters and esters with cyclic amines on the C‐7 endo‐nortropine derivatives of difluoroquinolone acid. All the synthesized compounds displayed good MIC against the Staphylococcus aureus when initially screened for Escherichia coli, S. aureus, Klebsiella pneumoniae, Acinetobacter baumannii, and Pseudomonas aeruginosa. The molecules were further evaluated for their antibacterial activity against fluoroquinolone‐resistant strains of S. aureus and for cytotoxic assay. Based on the results, five of the sixteen compounds displayed the potential to be developed further for treatment against fluoroquinolone‐resistant strains of S. aureus.     

Synthesis and antimicrobial evaluation of some cephem derivatives.

Two novel cephem derivative series were synthesized: 7-(D-alpha-aminophenyl-acetamido-)-3-methyl-3-cephem-4-carboxylic acid monohydrate (Cephalexin) derivatives and those of 7-amino-3-(1-methyl-1H-tetrazol-5-yl)-thio methyl-3-cephem-4-carboxylic acid (7-AMTCA). The antimicrobial activity of the prepared compounds was studied and compared to that of known cephalosporin antibiotics of the first generation against 12 standard strains and 189 clinical isolates of Gram-positive and Gram-negative microorganisms. The Cephalexin derivatives 4a-f show a narrow activity spectrum and are inactive while 5c and 5d are more active than the Cephalexin and Cephazolin antibiotics against clinically isolated S. aureus and S. epidermidis strains.     

Antibacterial Activity of Xanthones from Guttiferaeous Plants against Methicillin-resistant Staphylococcus aureus

Extracts of Garcinia mangostana (Guttiferae) showing inhibitory effects against the growth of S. aureus NIHJ 209p were fractionated according to guidance obtained from bioassay and some of the components with activity against methicillin-resistant Staphylococcus aureus (MRSA) were characterized. One active isolate, α-mangostin, a xanthone derivative, had a minimum inhibitory concentration (MIC) of 1.57?12.5 μg mL^?1. Other related xanthones were also examined to determine their anti-MRSA activity. Rubraxanthone, which was isolated from Garcinia dioica and has a structure similar to that of α-mangostin, had the highest activity against staphylococcal strains (MIC = 0.31?1.25 μg mL^?1), an activity which was greater than that of the antibiotic vancomycin (3.13?6.25 μg mL^?1). The inhibitory effect against strains of MRSA of two of the compounds when used in conjunction with other antibiotics was also studied. The anti-MRSA activity of α-mangostin was clearly increased by the presence of vancomycin; this behaviour was not observed for rubraxanthone. The strong in-vitro antibacterial activity of xanthone derivatives against both methicillin-resistant and methicillin-sensitive Staphylococcus aureus suggests the compounds might find wide pharmaceutical use.     

New azetidine-3-carbonyl-N-methyl-hydrazino derivatives of fluoroquinolones: synthesis and evaluation of antibacterial and anticancer properties

A series of nine new N-(substituted azetidine-3-carbonyl)-N-methyl-hydrazino derivatives at C-7 position of fluoroquinolones were designed and synthesized through multistep synthesis. The synthesized compounds were characterized by ¹H NMR, ¹³C NMR, ESI–MS and IR. The new compounds were tested for their in vitro antimicrobial and anti-proliferative activity. Out of the nine derivatives, compound 6i exhibited good antibacterial activity by inhibiting the growth of Methicillin-sensitive Staphylococcus aureus, Methicillin-resistant S. aureus and ATCC 35218 Escherichia coli (MIC: 0.25–16.00 μg/mL). Compounds 6c, 6g–h are displayed good growth inhibition against MCF-7 Breast carcinoma, HCT-116 Colon carcinoma and A549 Lung adenocarcinoma cell lines. Compound 6h is the most active against MCF-7 cell line with superior growth inhibition compared to ciprofloxacin and reference anticancer drug SAHA.     

Safranal epoxide – A potential source for diverse therapeutic applications

Safranal is an organic compound isolated from saffron oil. Photo epoxidation and thermal reactions of safranal can be a significant tool for the design of drugs to act as anticancer agents and potent chemoprevention. Safranal was subjected to oxidation reactions either thermally using m-chloroperbenzoic acid or photochemically with hydrogen peroxide. Photo chemically and thermally oxidation reaction gave the corresponding monoepoxy together with diepoxy derivatives. The primary tested of epoxide derivatives showed a moderate degree of DNA alkylation. Studies on the antimicrobial, especially Methicillin resistant Staphylococcus aureus (MRSA), showed high activity of safranal diepoxide (3) against the growth of bacteria Methicillin resistant Staphylococcus aureus (MRSA) more than safranal (1) and monoepoxide (2) respectively.The epoxidation products were tested against bacterium Methicillin resistant Staphylococcus aureus (MRSA).     

Microwave-assisted synthesis and antimicrobial activity of some imidazo[2,1-b][1,3,4]thiadiazole derivatives

A simple and efficient method was developed for the synthesis of 2,6-disubstituted-imidazo[2,1-b][1,3,4]thiadiazoles under microwave (MW) activation using 2-amino-5-substituted-1,3,4-thiadiazoles and appropriate bromo ketones as materials. All reactions demonstrated the benefits of MW reactions: convenient operation, short reaction time, and good yields. All derivatives were characterized by IR, NMR, and Mass spectroscopy. Antibacterial and antifungal activity was performed using cup plate method against Staphylococcus aureus, Klebsiella, and Candida albicans microorganisms. 2-(4-nitro benzyl)-6-(4-bromo phenyl)imidazo[2,1-b][1,3,4]thiadiazole (4Ce) was the only derivative which showed activity against Klebsiella at low micromolar concentration (5?μg/ml) with moderate zone of inhibition. And 2-(4-nitro benzyl)-6-(4-fluoro phenyl)imidazo[2,1-b][1,3,4]thiadiazole (4Cf) as the most potent antifungal active derivative at 50?μg/ml against C. albicans on comparison to standard fluconazole.     

Synthesis and preliminary antimicrobial evaluation of new 7-(N-pyrrolyl) derivatives of cephalosporins

A series of seven new cephalosporins was prepared for preliminary microbiological evaluation by N-acylation of 7-aminocephalosporanic acid with substituted N-pyrrolylcarboxylic acids via mixed anhydrides. The chemical structure of the compounds were confirmed by IR, 1H-NMR and mass spectral data. The 7-(N-pyrrolyl) cephalosporin derivatives were tested in vitro by the disc diffusion method upon 3 strains and subsequent determination of the minimal inhibitory concentration (MIC) of the most active ones upon 29 strains. The products of the series exhibited antibacterial activity. They showed selective potency against gram-positive and were practically inactive against gram-negative microorganisms. The compound 3-[(acetyloxy)methyl]-7-([2-[3-(ethoxycarbonyl)-2-methyl-5-phenyl-1H-1-pyrrolyl]acetyl]amino)-6-oxo-7,7a-dihydro-2H,6H-aceto[2,1-b][1,3]thiazine-4-carboxylic acid (4a) was outlined as more active than the reference cefazolin (CAS 23325-78-2) in regard to S. pyogenes and some strains of S. aureus, the MIC of 4a against S. pyogenes were at least 4-fold lower. The toxicological evaluations of the starting N-pyrrolylcarboxylic acids showed no acute toxicity.     

Synthesis and antibacterial activities of novel pleuromutilin derivatives bearing an aminothiophenol moiety

We synthesized a series of novel thioether pleuromutilin derivatives incorporating 2‐aminothiophenol moieties into the C14 side chain via acylation reactions under mild conditions. We evaluated the in‐vitro antibacterial activities of the derivatives against methicillin‐resistant Staphylococcus aureus (MRSA, ATCC 43300), Staphylococcus aureus (ATCC 29213) and Escherichia coli (ATCC 25922). The majority of the synthesized derivatives possessed moderate antibacterial activities. Compound 8 was found to be the most active antibacterial derivative against MRSA. We conducted docking experiments to understand the possible mode of interactions between compounds 8 , 9b , 11a and 50S ribosomal subunit. The docking results proved that there is a reasonable correlation between the binding free energy and the antibacterial activity. Compound 8 was evaluated for its in‐vivo antibacterial activity and showed higher efficacy than tiamulin against MRSA in mouse infection model.     

Synthesis and in vitro activity of new cephalosporin derivatives containing a benzoxazolone ring

New cephalosporin derivatives containing a benzoxazolone ring in the side acylamino chain are synthesized using chlorides of non-substituted and halogen substituted (2-benzoxazolone-3-yl) acetic acids for the acylation of the 7-aminodesacetoxy-cephalosporanic acid and 7-amino-cephalosporanic acid amino group. Some of these new compounds exhibit a biological activity higher than that of cephalexin and cephazolin against clinical strains of Staphylococcus aureus, Staphylococcus epidermidis and Streptococcus group A and B.     

Antibacterial Activity of some Medicinal Mangroves against Antibiotic Resistant Pathogenic Bacteria

The antibacterial activity of the leaves and bark of mangrove plants, Avicennia marina, A. officinalis, Bruguiera sexangula, Exoecaria agallocha, Lumnitzera racemosa, and Rhizophora apiculata was evaluated against antibiotic resistant pathogenic bacteria, Staphylococcus aureus and Proteus sp. Soxhlet extracts of petroleum ether, ethyl acetate, ethanol and water were prepared and evaluated the antibacterial activity using agar diffusion method. Most of the plant extracts showed promising antibacterial activity against both bacterial species. However, higher antibacterial activity was observed for Staphylococcus aureus than Proteus sp. The highest antibacterial activity was shown by ethyl acetate of mature leaf extracts of E. agallocha for Staphylococcus aureus. All ethyl acetate extracts showed higher inhibition against S. aureus while some extracts of chloroform, ethyl acetate and ethanol gave inhibition against Proteus sp. None of the petroleum ether and aqueous extracts showed inhibition against Proteus sp. All fresh plant materials did also show more antibacterial activity against both bacterial strains than did dried plant extracts. Antibacterial activity of fresh and dried plant materials reduced for both bacterial strains with time after extraction. Since L. racemosa and A. marina gave the best inhibition for bacterial species, they were used for further investigations. Charcoal treated plant extracts of L. racemosa and A. marina were able to inhibit both bacterial strains more than those of untreated plant extracts. Phytochemical screening of mature leaf, bark of L. racemosa and leaf extracts of A. marina has been carried out and revealed that leaf and bark contained alkaloids, steroids, triterpenoids and flavonoids. None of the above extracts indicate the presence of saponins and cardiac glycosides. Separated bands of extracts by TLC analysis showed antibacterial activity against S. aureus.     

In vitro prevention of the emergence of daptomycin resistance in Staphylococcus aureus and enterococci following combination with amoxicillin/clavulanic acid or ampicillin

Daptomycin is bactericidal against meticillin-resistant Staphylococcus aureus (MRSA), glycopeptide-intermediate-resistant S. aureus (GISA) and vancomycin-susceptible and -resistant enterococci. However, selection for daptomycin-resistant derivatives has occasionally been reported during therapy in humans. Here we evaluate whether selection for daptomycin-resistant S. aureus or enterococci could be prevented in vitro by combining daptomycin with amoxicillin/clavulanic acid, ampicillin, gentamicin or rifampicin. Six strains of S. aureus (four MRSA and two GISA) and four strains of enterococci (two Enterococcus faecalis and two Enterococcus faecium) were serially exposed in broth to two-fold stepwise increasing concentrations of daptomycin alone or in combination with a fixed concentration [0.25× minimum inhibitory concentration (MIC)] of either of the second agents. The daptomycin MIC was examined after each cycle. Exposure to daptomycin alone gradually selected for S. aureus and enterococci with an increased MIC. Gentamicin did not prevent the emergence of daptomycin-resistant bacteria. Rifampicin was also unable to prevent daptomycin resistance, although resistance was slightly delayed. In contrast, amoxicillin/clavulanic acid or ampicillin prevented or greatly delayed the selection of daptomycin-resistant mutants in S. aureus and enterococci, respectively. Addition of amoxicillin/clavulanic acid or ampicillin to daptomycin prevents, or greatly delays, daptomycin resistance in vitro. Future studies in animal models are needed to predict the utility of these combinations in humans.     

One‐pot synthesis and antiproliferative activity of novel double‐modified derivatives of the polyether ionophore monensin A

Monensin A ( MON ) is a polyether ionophore antibiotic, which shows a wide spectrum of biological activity. New MON derivatives such as double‐modified ester‐carbonates and double‐modified amide‐carbonates were obtained by a new and efficient one‐pot synthesis with triphosgene as the activating reagent and the respective alcohol or amine. All new derivatives were tested for their antiproliferative activity against two drug‐sensitive (MES‐SA, LoVo) and two drug‐resistant (MES‐SA/DX5, LoVo/DX) cancer cell lines, and were also studied for their antimicrobial activity against different Staphylococcus aureus and Staphylococcus epidermidis bacterial strains. For the first time, the activity of MON and its derivatives against MES‐SA and MES‐SA/DX5 were evaluated.     

Activity of ceftobiprole against methicillin-resistant Staphylococcus aureus strains with reduced susceptibility to daptomycin,linezolid or vancomycin,and strains with defined SCCmec types

Ceftobiprole is a broad-spectrum cephalosporin with activity against methicillin-resistant Staphylococcus aureus (MRSA) and Gram-negative pathogens including Pseudomonas aeruginosa. The aim of this study was to evaluate the activity of ceftobiprole against MRSA isolates with decreased susceptibility to daptomycin, linezolid or vancomycin as well as isolates from staphylococcal chromosome cassette mec (SCCmec) types I, II, III and IV. Overall, ceftobiprole demonstrated high potency against the 216 isolates tested, with MIC₅₀ and MIC₉₀ values (minimum inhibitory concentrations required to inhibit 50% and 90% of the isolates, respectively) of 1 mg/L and 2 mg/L (97.2% susceptible). The MIC₉₀ for ceftobiprole was 2 mg/L against the linezolid-non-susceptible, daptomycin-non-susceptible and vancomycin-intermediate (VISA and hVISA) subsets and was 1 mg/L against the vancomycin-resistant (VRSA) strains. The MIC_50/90 values for ceftobiprole were 2/4, 1/2, 2/2 and 1/1 mg/L against SCCmec types I, II, III and IV, respectively. SCCmec type I strains had the highest MICs, with six strains exhibiting a ceftobiprole MIC of 4 mg/L and 15 strains at 2 mg/L. Ceftobiprole demonstrated potent activity against MRSA, including subsets of isolates with reduced susceptibility to daptomycin, linezolid and vancomycin. The activity of ceftobiprole against these resistant phenotypes indicates that it may have clinical utility in the treatment of infections caused by multidrug-resistant S. aureus and across strains from prevalent SCCmec types.     

beta-Lactamase and beta-lactam antibiotics resistance in acinetobacter anitratum (syn: A. calcoaceticus).

The cephalosporin beta-lactamase (cephalosporinase) produced by Acinetobacter was studied. The enzyme was partially purified by means of column chromatography and its properties were investigated. The enzyme was induced by benzylpenicillin, 6-aminopenicillanic acid and cephaloridine. Its molecular weight is 30,000 its optimal temperature 40C, and its optimal pH 7.25 similar to 7.50. Substrate specificity studies using various cephalosporins and penicillins, showed that the enzyme functioned as a cephalosporinase rather than penicillinase.     

Synthesis of new 3-aryl-4-(3-aryl-4,5-dihydro-1H-pyrazol-5-yl)-1-phenyl-1H-pyrazole derivatives as potential antimicrobial agents

New (E)-1-aryl-3-(3-aryl-1-phenyl-1H-pyrazol-4-yl)prop-2-en-1-ones 6 (pyrazolic chalcones) were synthesized from Claisen–Schmidt reaction of 3-aryl-1-phenylpyrazol-4-carboxaldehydes 4 with several acetophenone derivatives 5. Subsequently, the cyclocondensation reaction of chalcones 6 with phenylhydrazine in acetic acid medium afforded the new 3-aryl-4-(3-aryl-4,5-dihydro-1H-pyrazol-5-yl)-1-phenyl-1H-pyrazoles 7. The synthesized compounds were characterized by spectral studies and evaluated for their in vitro antibacterial activity against three pathogenic bacterial strains, Staphylococcus aureus, Escherichia coli, and Pseudomonas aeruginosa, and in vitro antifungal activity against three pathogenic fungal strains Aspergillus flavus, Chrysosporium keratinophilum, and Candida albicans.     

Antimicrobial Activity of Some 1,2-Benzisothiazoles Having a Benzenesulfonamide Moiety

Some sulfonamide and sulfonylurea derivatives of unsubstituted and 5-methylsubstituted 1,2-benzisothiazole were studied in vitro for their antimicrobial properties against bacteria and fungi. Compounds 7 and 8 exhibited good antibacterial activity against Gram positive bacteria. A strong synergism was observed when their growth-inhibitory effect was assayed in combination with trimethoprim by using Bacillus subtilis and Staphylococcus aureus as test microorganisms. The antimycotic action of benzenesulfonylurea derivative 9 was very marked for Madurella mycetomatis and dermatophytes Epidermophyton floccosum, Microsporum gypseum and Trichophyton spp. Structure-activity relations are discussed.     

In Vitro and In Vivo Antibacterial Activity of Gliotoxin Alone and in Combination with Antibiotics against Staphylococcus aureus

Multidrug-resistant bacteria such as methicillin-resistant Staphylococcus aureus (MRSA) is one of the major causes of hospital-acquired and community infections and pose a challenge to the human health care system. Therefore, it is important to find new drugs that show activity against these bacteria, both in monotherapy and in combination with other antimicrobial drugs. Gliotoxin (GT) is a mycotoxin produced by Aspergillus fumigatus and other fungi of the Aspergillus genus. Some evidence suggests that GT shows antimicrobial activity against S. aureus in vitro, albeit its efficacy against multidrug-resistant strains such as MRSA or vancomycin-intermediate S. aureus (VISA) strainsis not known. This work aimed to evaluate the antibiotic efficacy of GT as monotherapy or in combination with other therapeutics against MRSA in vitro and in vivo using a Caenorhabditis elegans infection model.     

Antibacterial activity of 15‐residue lactoferricin derivatives

Abstract: Lactoferricins are a class of antibacterial peptides isolated after gastric‐pepsin digest of the mammalian iron‐chelating‐protein lactoferrin. For investigation of antibacterial activity, we prepared short synthetic derivatives of bovine, human, caprine, murine and porcine lactoferricins with 15‐amino‐acid residues of high sequence homology. The peptides corresponded to amino‐acid residues 17–31 of the mature bovine lactoferrin. Only the bovine and caprine derivatives displayed measurable antibacterial activity, with the bovine one having a minimal inhibitory concentration of 24 µm and being 10 times more active than the caprine one against Escherichia coli. An alanine‐scan of the bovine lactoferricin derivative was performed to identify specific amino acids that were important for the antibacterial activity. We found that neither of the two tryptophan residues (Trp 6 and Trp 8) present in the bovine lactoferricin derivative could be replaced by alanine without a major loss of antibacterial activity. The other lactoferricin derivatives tested contained only one tryptophan residue (Trp 6). Modified human, caprine and porcine lactoferricin derivatives containing two tryptophan residues (Trp 6 and Trp 8) displayed minimal inhibitory concentrations of 74, 174 and 219 µm , respectively, which represented up to a six‐fold increase in antibacterial activity. The alanine‐scan also revealed that the antibacterial activity was increased when acetamidomethyl‐protected cysteine and unprotected glutamine (Cys 3 and Gln 7) were replaced with alanine. Only the bovine lactoferricin derivative and a few of its alanine‐modified derivatives displayed measurable activity against Staphylococcus aureus.