Synthesis and antibacterial activity of the new 9-aminoacridine, 10,11-dihydro-5H-dibenzo[b,f]azepine, polyfluoro 5,6-dihydro-1,3,5-oxadiazine derivatives]

Screening among 9-aminoacridine, 10,11-dihydro-5H-dibenz[b, f]azepine and polyfluoro 5,6-dihydro-1,3,5-oxadiazine derivatives allowed to isolate compounds with potential antibacterial activity. Schemes of the active compounds synthesis are given. The most important is the estimation of the oxydiazines activity against gram-positive microorganisms including methicillin-resistant staphylococci. Special attention is paid to the activity of iminodibenzyl derivatives against multiresistant gram-negative microorganisms.     

Identification of Nor-��-Lapachone Derivatives as Potential Antibacterial Compounds against Enterococcus faecalis Clinical Strain

A broad-spectrum antibiotic therapy has led to medical complications and emergence of multiresistant bacteria including Enterococcus faecalis. In this study, we designed, synthesized, and evaluated the antibacterial activity of 13 nor-β-lapachone derivatives against a drug resistant E. faecalis strain. Two triazole substituted compounds (1e = 8 μg/ml and 1c = 16 μg/ml) and the non-substituted derivative (1a = 8 μg/ml) were promising compared to chloramphenicol (12 μg/ml), an antibiotic currently available in the market. We also performed a structure-activity relationship analysis using a molecular modeling approach that pointed the low HOMO energy values; HOMO density concentrated on the nor-β-lapachone ring, lipophilicity, solubility and number HBA as important stereoelectronic features for the antibacterial profile. In addition the triazole compounds presented low theoretical toxicity profile, and drug-score higher than commercial antibiotics also fulfilling the Lipinski "Rule of Five", which pointed them as promising candidates for further studies in infections caused by multiresistant E. faecalis hospital strains.     

The synthesis and antibacterial activity of totarol derivatives. Part 3: Modification of ring-B

Ring-B derivatization of totarol (1) afforded the series of compounds 2-22 which were screened in vitro against: beta-lactamase-positive and high level gentamycin-resistant Enterococcus faecalis, penicillin-resistant Streptococcus pneumoniae, methicillin-resistant Staphylococcus aureus (MRSA), and multiresistant Klebsiella pneumoniae. Several of the derivatives retained much of the antibacterial activity of totatol against the first three of these organisms (all gram-positive), but none was more active. The gram-negative Klebsiella was resistant to all compounds examined. Totarol (1) was shown to uncouple oxidative phosphorylation in isolated mitochondria at 50 microM.     

Anthraquinones from the stem bark of Stereospermum zenkeri with antimicrobial activity

Two anthraquinones, zenkequinones A and B were isolated from the stem bark of Stereospermum zenkeri together with known sterequinone-F, p-coumaric acid, sitosterol-3-O-beta-D-glucopyranoside and 3beta-hydroxyolean-12-en-28-O-beta-D-glucopyranoside. Their structures were established by spectroscopic methods. The antimicrobial activity of the isolated compounds was evaluated against six multiresistant strains of pathogens. Zenkequinone B showed the best antibacterial activity (MIC 9.50 microg/ml) against gram-negative Pseudomonas aeruginosa.     

The synthesis and antibacterial activity of totarol derivatives. Part 2: Modifications at C-12 and O-13

Alterations of the C-12 and C-13 aromatic ring substituents of totarol (1) afforded the series of derivatives 2-14, and introduction of substituents at C-12 gave exclusively 2a-14a. The majority of these analogues were tested in vitro against the following organisms: beta-lactamase-positive and high level gentamycin-resistant Enterococcus faecalis, penicillin-resistant Streptococcus pneumoniae, methicillin-resistant Staphylococcus aureus (MRSA), and multiresistant Klebsiella pneumoniae. The results were evaluated in terms of structure-activity relationship which reveals that: (a) the phenolic moiety at C-13, in general, is essential for antibacterial activity at < 32 microg/mL against gram-positive species, and (b) derivatization at C-12 has an undesirable effect on the antibacterial activity of this class of compounds, while (c) all compounds tested are ineffective against the gram-negative Klebsiella pneumoniae.     

Omega-pyridiniumalkylethers of steroidal phenols: new compounds with potent antibacterial and antiproliferative activities

Novel omega-pyridiniumalkylethers of two steroidal phenols were synthesized as compounds with potential antimicrobial activity. 3-Hydroxy-estra-1,3,5(10)-triene-17-one and 1-hydroxy-4-methyl-estra-1,3,5(10)-triene-17-one were reacted with omega,omega'-dibromoalkanes to omega-bromoalkoxy-estra-1,3,5(10)-trienes followed by reaction with pyridine to obtain the desired steroidal omega-pyridiniumalkoxy compounds as bromides. Their antimicrobial activity against strains of multiresistant Staphylococcus aureus (MRSA), a vancomycin resistant Enterococcus faecalis and fast growing mycobacteria depends clearly on the length of the alkyl chain. A strong broadband activity has been found for the compounds with eight or 10 C-atoms; in some cases better than ciprofloxacin or cetylpyridinium salts. In addition, the antiproliferative and cytotoxic activity depends on the chain length, too. The differentiation between antibacterial and cytotoxic activity is better for the steroid hybrid molecules than the cetylpyridinium salts. These new compounds can serve as lead compounds for further optimization.     

Chemical composition and biological activity of Laennecia schiedeana

The chemical study of Laennecia schiedeana afforded three sterols, five diterpenes, five flavonoids, three caffeoyl derivatives of quinic acid, and two triterpenes. Evaluation of the cytotoxic activity of the extracts and isolated metabolites showed that 15-methoxy-16-oxo-15,16H-strictic acid was the most active compound [(15.05 +/- 2.2) microg/mL against U-251 cells]. In antibacterial assays the acetonic extract of leaves was the only active extract exhibiting its highest effect against the multiresistant Staphylococcus epidermidis (MIC 0.25 mg/mL). The anti-inflammatory activity observed was mild in the extracts and not relevant in the isolated compounds.     

Solution structure by nuclear magnetic resonance of the two lantibiotics 97518 and NAI‐107

Lantibiotics 97518 and NAI‐107, produced by the related genera Planomonospora and Microbispora respectively, are members of a family of nisin‐related compounds. They represent promising compounds to treat infections caused by multiresistant Gram‐positive pathogens. Despite their similar structure and a similar antibacterial spectrum, the two lantibiotics exhibit significant differences in their potency. To gain an insight into the structure–activity relationships, their conformational properties in solution are determined by NMR. After carrying out an NOE analysis of 2D ¹H NMR spectra, high‐resolution 3D structures are determined using molecular dynamics simulations. Copyright © 2011 European Peptide Society and John Wiley & Sons, Ltd.     

Antiprotozoal activity of bicycles featuring a dimethylamino group at their bridgehead

Several dimethylamino-derivatives of the new compound-class 3-azabicyclo[3.2.2]nonanes were prepared. For better comparison of activity also a few analogues of bicyclo[2.2.2]octanes and 2-azabicyclo[3.2.2]nonanes were synthesized. Their activities were examined in vitro against the multiresistant K₁ strain of Plasmodium falciparum and against Trypanosoma brucei rhodesiense (STIB 900). A couple of the newly synthesized compounds showed promising antiprotozoal activity and selectivity. The results of the biological tests of the novel compounds were compared with the activities of already synthesized compounds and of drugs in use. Structure–activity relationships were discussed.     

Benzo[f]naphtyridones: a new family of topical antibacterial agents active on multi-resistant Gram-positive pathogens

The synthesis and antibacterial activity of benzo[f][1,7]naphtyridone derivatives are reported. These compounds are potent antibacterial agents with a Gram-positive spectrum of activity. They are active against multi-resistant cocci, especially Staphylococcus aureus strains. Their physico-chemical and biological properties make them particularly suitable for topical antibacterial use.     

Chemical Composition and Antimicrobial Activity of the Essential Oil from Aerial Parts and Roots of Eryngium barrelieri Boiss. and Eryngium glomeratum Lam. from Tunisia

The study of chemical composition and biological activity of unexplored essential oils may open new perspectives on their potential use in facing major health concerns such as drug‐resistant infections. The present study investigates the chemical composition and antimicrobial effects of previously unstudied essential oils obtained from genus Eryngium: Eryngium glomeratum Lam . and Eryngium barrelieri Boiss . The chemical compositions of the essential oils from aerial parts and roots of both species were studied using GC and GC/MS analytical technics. The analysis led to the identification of 102 compounds totalizing 85 – 94% of all detected compounds. Essential oils were characterized by the predominance of oxygenated sesquiterpenes. The oils obtained from aerial parts were tested against 36 microbial strains by agar dilution method and showed minimum inhibitory concentrations (MIC) in the range of 2 – 625 μg/ml. A strong antibacterial activity against multiresistant Pseudomonas aeruginosa was observed especially from E. glomeratum essential oil with MIC value up to 2 μg/ml. These findings give significant information about the pharmacological activity of these essential oils, which suggest their potential use to develop new remedies, or as sources of active compounds.     

Menadione (vitamin K) enhances the antibiotic activity of drugs by cell membrane permeabilization mechanism

Menadione, vitamin K3, belongs to the class of lipid-soluble vitamins and lipophilic substances as menadione cause disturbances in the bacterial membrane, resulting in damage to the fundamental elements for the integrity of the membrane, thus allowing increased permeability. Accordingly, the aim of this study was to evaluate in vitro the antibiotic-modifying activity of menadione in multiresistant strains of Staphylococcus aureus, Pseudomonas aeruginosa and Escherichia coli, with a gradual increase in its subinhibitory concentration. In addition, menadione was compared with cholesterol and ergosterol for similarity in mechanism of drug modulatory action. Antibiotic-modifying activity and antibacterial effect were determined by the broth microdilution assay. Menadione, cholesterol and ergosterol showed modulatory activity at clinically relevant concentrations, characterizing them as modifiers of bacterial drug resistance, since they lowered the MIC of the antibiotics tested. This is the first report of the antibacterial activity of menadione and its potentiation of aminoglycosides against multiresistant bacteria.     

Anti-malarial activity of N(6)-substituted adenosine derivatives. Part I

The synthesis and biological evaluation of novel N(6)-substituted adenosine derivatives is reported. The first series of compounds was obtained using an established procedure for the nucleophilic substitution of a 1-(6-chloro-purin-9-yl)-beta-D-1-deoxy-ribofuranose with various amines. In addition, attachment of two different amino-functionalised spacer arms at the N(6)-position of adenosine enabled derivatisation by an innovative polymer-assisted protocol. Thus, we were able to prepare three series of substituted derivatives that displayed activity versus the multiresistant Plasmodium falciparum strain Dd2 in cell culture experiments.     

Antibacterial activity of 3-methylbenzo[d]thiazol-methylquinolinium derivatives and study of their action mechanism

The increasing incidence of multidrug resistant bacterial infection renders an urgent need for the development of new antibiotics. To develop small molecules disturbing FtsZ activity has been recognized as promising approach to search for antibacterial of high potency systematically. Herein, a series of novel quinolinium derivatives were synthesized and their antibacterial activities were investigated. The compounds show strong antibacterial activities against different bacteria strains including MRSA, VRE and NDM-1 Escherichia coli. Among these derivatives, a compound bearing a 4-fluorophenyl group (A2) exhibited a superior antibacterial activity and its MICs to the drug-resistant strains are found lower than those of methicillin and vancomycin. The biological results suggest that these quinolinium derivatives can disrupt the GTPase activity and dynamic assembly of FtsZ, and thus inhibit bacterial cell division and then cause bacterial cell death. These compounds deserve further evaluation for the development of new antibacterial agents targeting FtsZ.     

Synthesis and antibacterial activity of new carbapenems containing isoxazole moiety

The synthesis and biological activity of a series of new 1beta-methylcarbapenems 1a-g containing 5'-isoxazolopyrrolidin-3'-ylthio derivatives as C-2 side chain are described. Most compounds exhibited potent and well-balanced antibacterial activity as well as high stability to DHP-I comparable to that of meropenem. 1e and 1c showed the best combination of antibacterial activity and stability to DHP-I, respectively.     

Synthesis and QSAR studies of pyrimido[4,5-d]pyrimidine-2,5-dione derivatives as potential antimicrobial agents

A number of pyrimido[4,5-d]pyrimidine-2,5-dione derivatives were synthesized and screened for antibacterial and antifungal activities. All the synthesized compounds showed the potent antimicrobial activity. The quantitative structure-activity relationship investigation was applied to find a correlation between the different physicochemical parameters of the compounds studied and their biological activity.     

Hybrid molecules of estrone: new compounds with potential antibacterial, antifungal, and antiproliferative activities

New hybrid molecules of estrone were synthesized as compounds indicating promising biological activity (antibacterial, antimycobacterial, antifungal, and antiproliferative). The prepared molecules contained various heterocyclic units (pyridine, benzylsulfanyl derivatives of pyridine or derivatives of tetrazole) linked to estrone by n-heptyl bridges. The compounds with charge on molecule (the hybrid pyridinium or benzylsulfanylpyridinium salts) exhibited significant biological activity (antibacterial, antimycobacterial, antifungal, and antiproliferative). On the other hand, the compounds not in the form of salts (omega-(1-phenyl-5-tetrazolylthio)heptylethers of estrone) were inactive. The antimycobacterial activities of three different series of tetrazole derivatives (i.e., the hybrid molecules with estrone, tetrazole-5-thiols, and 5-benzylsulfanyl-1-phenyltetrazoles) with the same substituents on phenyl ring were compared. Amongst them, the 5-benzylsulfanyl-1-phenyltetrazoles were the most potent.     

Treatment with Hypericum perforatum L. does not trigger decreased resistance in Staphylococcus aureus against antibiotics and hyperforin.

Most scientific investigations of Hypericum perforatum L. (Saint John's wort) concentrated on its antidepressant activity. Only recently, its antibacterial activity against multiresistant Staphylococcus aureus led to speculations regarding the use of hyperforin, an antibacterial principle of hypericum, as an antibiotic. In the present investigation, we show that Staphylococcus aureus is able to acquire a resistance against hyperforin which did not lead to a cross resistance against clinically used antibiotics. Resistance development does not take place, however, at concentrations as low as they are found in human blood plasma during antidepressant treatment with 900 mg Hypericum extract/day.     

苯并异噻唑啉酮类化合物的生物活性研究

对合成的5种苯并异噻唑啉酮类化合物进行了生物活性研究。抑菌试验结果表明,化合物a与化合物b对大肠杆菌最小抑菌浓度为12.5mg/L。对金黄色葡萄球菌都表现出良好的抑菌活性。对亚心形扁藻,蛋白核小球藻,球等鞭金藻,化合物都有抑制其生长的活性,亚心形扁藻耐受性最高,球等鞭金藻的耐受性最低,蛋白核小球藻的耐受性居中。     

四氢蒽醌类化合物结构及其生物活性研究进展

四氢蒽醌类化合物是一类比较少见的天然结构,以微生物次生代谢产物居多,少量来源于植物,具有细胞毒活性、抗菌活性、抗疟原虫等生物活性。本文主要从四氢蒽醌类化合物及其衍生物的结构和生物活性两方面来对天然四氢蒽醌化合物进行综述,共综述了54个四氢蒽醌类化合物,45个来源于微生物,9个来源于植物南山花的根中,其中altersolanol A具有很好的抗肿瘤活性,是一个有很大吸引力的抗癌先导化合物。通过对四氢蒽醌类化合物的综述,为四氢蒽醌类化合物的进一步研究和开发提供依据。