Synthesis and antibacterial activity of novel 4-pyrrolidinylthio carbapenems Part IV. 2-Alkyl substituents containing cationic heteroaromatics linked via a C-C bond

The synthesis and biological activity of a novel series of 2-alkyl-4-pyrrolidinylthio-beta-methylcarbapenems containing a variety of cationic heteroaromatic substituents linked via a C-C bond is described. As a result of these studies, we selected FR21818 (In) as a candidate compound for development. FR21818 exhibited a well balanced spectrum of antibacterial activity, including Pseudomonas aeruginosa and methicillin-resistant Staphylococcus aureus (MRSA), excellent urinary recovery, good stability against renal dehydropeptidase-I (DHP-I). no antigenicity and mutagenicity, weak toxicities, and good efficacy and therapeutic effect on mice systemic infections. Affinities to PBP's, permeability of outer membrane, and plasma levels in mice, dog, and cynomolgous monkey of FR21818 are also reported.     

New Arylazo-Based (Chromene-Thiazole) Hybrids as Potential MRSA Inhibitors

A three-component protocol was established to efficiently synthesize (chromene-thiazole) and related arylazo analogs in good to excellent yields. The desired products were prepared by reacting the appropriate salicylaldehydes, 2-cyanothioacetamide, and chloroacetone or hydrazonyl chlorides. Using piperidine as a mediator in ethanol at 80 °C for 4–6 h, the three-component protocol produce the target hybrids in 87–96 % yields. The newly synthesized products showed a broad range of antibacterial activity. The addition of an arylazo unit at the chromene-C6 position significantly improved the antibacterial activity, while the impact of adding an arylazo group at the thiazole-C5 position varied based on the electronic characteristics of the para-substituted arene unit. Generally, series that is linked to two arylazo units, one at chromene-C6 and the other at thiazole-C5, showed the best activity. Some new hybrids showed effective antibacterial activity than ciprofloxacin with MIC/MBC values up to 1.9/3.9 μM against S. aureus and E. coli. Additionally, they demonstrated better effectiveness against MRSA ATCC:33591 and ATCC:43300 compared to linezolid, with MIC/MBC values up to 4.0/16.1 and 3.9/15.6 μM, respectively. The data predicted for the physicochemical properties, lipophilicity, pharmacokinetics, and drug-likeness of new arylazo-based chromene-thiazole hybrids evaluated by SwissADME. As a result of the above, products that are linked to two arylazo units can be considered drug-like scaffolds.     

Beta-keto-ester chemistry and ketolides. Synthesis and antibacterial activity of 2-halogeno, 2-methyl and 2,3 enol-ether ketolides

The effect of 2,3 modifications on the antibacterial activity of ketolides was evaluated by introducing substituents in position 2 and converting the C-1, C-2, C-3 beta-keto-ester into stable 2,3 enol-ether or 2,3 anhydro derivatives. Introduction of a fluorine in C-2 is beneficial with regard to the overall antibacterial spectrum whereas the enol-ether and 2,3 unsaturated compounds, as well as the bulky gem dimethyl or 2-chloro derivatives, are less active particularly against erythromycin resistant strains. A 2-fluoro ketolide derivative demonstrates good antibacterial activity and in vivo efficacy against multi-resistant Streptococcus pneumoniae. Compared to azithromycin against Haemophilus influenzae, this compound is equivalent in vitro and slightly more active in vivo. These results demonstrate that within the ketolide class, to retain good antibacterial activity, position 2 needs to remain tetrahedral and tolerates only very small substituents such as fluorine.     

肠球菌E4及其抑菌产物特性的研究

目的获得抑制微生物生长的菌株。方法根据形态学和生理生化学特性进行菌种鉴定;采用牛津杯法测定抑菌谱和抑菌物质的理化特性。结果排除了过氧化氢和有机酸的作用,该菌发酵上清液对苏云金杆菌、枯草杆菌、大肠埃希菌、鸡白痢沙门菌等有抑制作用。根据菌株的生理生化特征,该菌株初步定为肠球菌属,定名为E4（Enterococcus sp．）。所产抑菌物质具有较好的热稳定性,在酸性条件下稳定且活性高。结论分离筛选了1株可产抑菌物质的肠球菌,其产生的抑菌物质具有良好的生物化学特性和广谱的抑菌能力。     

Enols as potent antibacterial agents.

This paper describes the discovery of alpha-trifluoroketoacetamides as potent antibacterial agents against Gram-positive organisms. The initial SAR indicates that the aryl ethyl side chain is essential in maintaining antibacterial activity. The SAR observations have been utilized to design a bioisostere for the alpha-trifluoroketoacetamide with good activity against Gram-positive organisms.     

A comparison of the sensitivity of wound-infecting species of bacteria to the antibacterial activity of manuka honey and other honey

Both honey and sugar are used with good effect as dressings for wounds and ulcers. The good control of infection is attributed to the high osmolarity, but honey can have additional antibacterial activity because of its content of hydrogen peroxide and unidentified substances from certain floral sources. Manuka honey is known to have a high level of the latter.
Seven major wound-infecting species of bacteria were studied to compare their sensitivity to the non-peroxide antibacterial activity of manuka honey and to a honey in which the antibacterial activity was primarily due to hydrogen peroxide. Honeys with activity in the middle of the normal range were used. A comparison of the median response of the various species of bacteria showed no significant difference between the two types of activity overall, but marked differences between the two types of activity in the rank order of sensitivity of the seven bacterial species. The non-peroxide antibacterial activity of manuka honey at a honey concentration of 1.8% (v/v) completely inhibited the growth of Staphylococcus aureus during incubation for 8 h. The growth of all seven species was completely inhibited by both types of honey at concentrations below 11% (v/v).     

A comparison of the sensitivity of wound-infecting species of bacteria to the antibacterial activity of manuka honey and other honey.

Both honey and sugar are used with good effect as dressings for wounds and ulcers. The good control of infection is attributed to the high osmolarity, but honey can have additional antibacterial activity because of its content of hydrogen peroxide and unidentified substances from certain floral sources. Manuka honey is known to have a high level of the latter. Seven major wound-infecting species of bacteria were studied to compare their sensitivity to the non-peroxide antibacterial activity of manuka honey and to a honey in which the antibacterial activity was primarily due to hydrogen peroxide. Honeys with activity in the middle of the normal range were used. A comparison of the median response of the various species of bacteria showed no significant difference between the two types of activity overall, but marked differences between the two types of activity in the rank order of sensitivity of the seven bacterial species. The non-peroxide antibacterial activity of manuka honey at a honey concentration of 1.8% (v/v) completely inhibited the growth of Staphylococcus aureus during incubation for 8 h. The growth of all seven species was completely inhibited by both types of honey at concentrations below 11% (v/v).     

家蝇蛆抗菌肽提取工艺研究

蝇蛆抗菌肽多有广谱抗菌、抗癌等功能,是很好的天然抗菌药物来源,但由于得率较低,目 前对其产品开发的研究较少。以家蝇Musca domestica干蝇蛆为原料,利用加热-层析法和海藻酸吸附法2种工艺提取蝇蛆抗菌肽。结果表明：加热-层析法快速、简便,抗菌肽提取得率达0.26％,是海藻酸吸附法提取抗菌肽得率的5.2倍。提取的家蝇抗菌肽主要是分子量6.2～17.2 kD、等电点5.59～5.91的弱酸性小分子多肽,其热稳定性高,能杀灭枯草杆菌Bacillus subtilis等多种革兰氏阳性菌。加热-层析法能有效去除外源性蛋白酶,保证肽类产品的稳定性,同时还能提取出非蛋白类的抗菌成分,提示其对开发具有高附加值的抗菌产品将会有良好的应用前景。     

Synthesis, in vitro, and in vivo antibacterial activity of nocathiacin I thiol-Michael adducts

The synthesis and antibacterial activity of a series of nocathiacin I derivatives (4-20) containing polar water solubilizing groups is described. Thiol-Michael adducts containing acidic polar groups have reduced antibacterial activity whereas those with basic polar groups have retained very good antibacterial activity.     

A novel ketolide class: Synthesis and antibacterial activity of a lead compound

Synthesis and antibacterial activity of a new class of ketolide antibiotics, exemplified by the prototype GW680788X (1), are described. The structure of (1) has been elucidated by spectroscopic analysis. The good antibacterial activity shown by (1) in comparison with clarithromycin prompted us to consider this compound as a lead molecule for further exploration.     

A series of heterocyclic inhibitors of phenylalanyl-tRNA synthetases with antibacterial activity

A series of novel heterocyclic analogues have been synthesized and evaluated for their ability to inhibit phenylalanyl-t-RNA synthetases and act as antibacterial agents. Several analogues have good antibacterial activity against Staphylococcus aureus.     

Functionalization of cotton fabric with PVP/ZnO nanoparticles for improved reactive dyeability and antibacterial activity

Poly-N-vinyl-2-pyrrolidone functionalization was done for improved the dyeability of dichlorotriazine dyes on cotton fabric. The synthesized ZnO nanoparticles were padded on functionalized cotton fabrics to improve antibacterial activity. The modification effects were characterized by FTIR, XRD, SEM and EDX studies. The antibacterial activity was done against Staphylococcus aureus and Escherichia coli bacterium. The dye exhaustion and fastness properties were analyzed for dyeing with sodium chloride, sodium sulfate and trisodium citrate bio-salt as exhausting agents. The functionalized cotton fabric showed improved dye uptake and good fastness properties. Poly-N-vinyl-2-pyrrolidone with ZnO nanoparticles padded fabrics showed very good antibacterial activity.     

Anti-tubercular agents. Part IV: Synthesis and antimycobacterial evaluation of nitroheterocyclic-based 1,2,4-benzothiadiazines

In continuation of our earlier work on benzothiadiazines, we have prepared a series of nitrofuran, nitrothiophene and arylfuran coupled benzothiadiazines and evaluated them for antimycobacterial and antibacterial activities. One of the compounds 2f has shown good in vitro antimycobacterial activity. All the synthesized compounds have shown moderate to good antibacterial activity.     

Exploring Left-Hand-Side substitutions in the benzoxazinone series of 4-amino-piperidine bacterial type IIa topoisomerase inhibitors

An SAR survey at the C-6 benzoxazinone position of a novel scaffold which inhibits bacterial type IIa topoisomerase demonstrates that a range of small electron donating groups (EDG) and electron withdrawing groups (EWG) are tolerated for antibacterial activity. Cyano was identified as a preferred substituent that affords good antibacterial potency while minimizing hERG cardiac channel activity.     

Designing Chimeric Peptides: A Powerful Tool for Enhancing Antibacterial Activity

Chimeric peptides containing short sequences derived from bovine Lactoferricin (LfcinB) and Buforin II (BFII) were synthetized using solid-phase peptide synthesis (SPPS) and characterized via reversed-phase liquid chromatography and mass spectrometry. The chimeras were obtained with high purity, demonstrating their synthetic viability. The chimeras’ antibacterial activity against Gram-positive and Gram-negative strains was evaluated. Our results showed that all the chimeras exhibited greater antibacterial activity against the evaluated strains than the individual sequences, suggesting that chemical binding of short sequences derived from AMPs significantly increased the antibacterial activity. For each strain, the chimera with the best antibacterial activity exerted a bacteriostatic and/or bactericidal effect, which was dependent on the concentration. It was found that: (i) the antibacterial activity of a chimera is mainly influenced by the linked sequences, the palindromic motif RLLRRLLR being the most relevant one; (ii) the inclusion of a spacer between the short sequences did not significantly affect the chimera's synthesis process; however, it enhanced its antibacterial activity against Gram-negative and Gram-positive strains; on the other hand, (iii) the replacement of Arg with Lys in the LfcinB or BFII sequences improved the chimeras’ synthesis process without significantly affecting their antibacterial activity. These results illustrate the great importance of the synthesis of chimeric peptides for the generation of promising antibacterial peptides.     

In vitro antibacterial activity of Chilean red wines against Helicobacter pylori

The antibacterial activity of sixteen Chilean red wines (Cabernet Sauvignon, Cabernet Merlot, Cabernet Organic and Pinot Noir), and the active extracts of two randomly selected wines were assayed for their antibacterial activity on six strains of Helicobacter pylori isolated from gastric biopsies. The active fraction of the wines was obtained by dichloromethane extraction, and the antibacterial activity of the wines and extracts was evaluated by an agar diffusion method. All the red wines studied showed some antibacterial activity on the six strains of H. pylori, although the strains were heterogeneous in their susceptibility to each particular wine. The active fraction of the two wines selected also showed good activity against the strains tested. The main active compound was identified as resveratrol. The results presented indicate that Chilean red wines have antibacterial activity against H. pylori, which depends mainly on the presence of resveratrol.     

中国家蚕抗菌肽人工合成类CMⅣ基因在甜菜夜蛾虫体中的表达

将人工合成的中国家蚕抗菌肽类CMⅣ基因与抗菌肽信号肽基因连接 ,经EcoRⅠ、HindⅢ双酶切后 ,克隆于pFASTBacⅠ的EcoRⅠ、HindⅢ酶切位点之间 ,得到重组转座载体pFASTBac ABP ,经测序证明阳性克隆正确。将重组转座载体转化HD1 0Bac大肠杆菌 ,得到重组Bacmid ABP。将重组Bacmid转染sf2 1细胞及感染甜菜夜蛾 (Laphygmaexigua)幼虫 ,在培养细胞上清及虫体血淋巴中均测到抗菌活性。经Northernblotting证明感染甜菜夜蛾幼虫中有类CMⅣmRNA的存在。且表达产物在酸性电泳中电泳行为与天然抗菌肽CMⅣ组分相似。为进一步利用昆虫细胞及虫体生产抗菌肽药物打下了基础。     

新型抗菌肽——表面活性素、伊枯草菌素和丰原素

表面活性素（surfactin）、伊枯草菌素（iturin）和丰原素（fengycin）是一类主要由革兰阳性芽胞杆菌通过非核糖体合成途径产生的抗菌肽,一般是由1个β-羟基脂肪酸与7～10个氨基酸肽链以酰胺键连接而成的环肽,具有抗细菌、抗真菌、抗病毒、抗肿瘤等生物活性,在医疗方面具有良好的应用前景。目前,人们对这3种新型抗菌肽在医药领域中的研究进展所知甚少,故本文对其发现历史、结构特点、作用机制、生物合成和应用价值进行阐述,为后续研究提供借鉴。     

Polyelectrolyte complexes between (cross-linked) N-carboxyethylchitosan and (quaternized) poly[2-(dimethylamino)ethyl methacrylate]: preparation, characterization, and antibacterial properties

Novel polyelectrolyte complexes (PECs) between N-carboxyethylchitosan (CECh) and well-defined (quaternized) poly[2-(dimethylamino)ethyl methacrylate] (PDMAEMA) have been obtained. The modification of chitosan into CECh allows the preparation of PECs in a pH range in which chitosan cannot form complexes. The CECh/PDMAEMA complex is formed in a narrow pH range around 7. The quaternization of the tertiary amino groups of PDMAEMA enables complex formation with CECh both in neutral and in alkaline medium. Cross-linked CECh is also capable of forming complexes with (quaternized) PDMAEMA. The antibacterial activity of (cross-linked) CECh, (quaternized) PDMAEMA, and their complexes against Escherichia coli has been evaluated. In contrast to (quaternized) PDMAEMA, (cross-linked) CECh exhibits no antibacterial activity. The complex formation between cross-linked CECh and (quaternized) PDMAEMA results in a loss of the inherent antibacterial activity of the latter in neutral medium. In acidic medium, the complexes exhibit strong antibacterial activity due to complex disintegration and release of (quaternized) PDMAEMA.     

Triaminotriazine DNA helicase inhibitors with antibacterial activity

Screening of a chemical library in a DNA helicase assay involving the Pseudomonas aeruginosa DnaB helicase provided a triaminotriazine inhibitor with good antibacterial activity but associated cytotoxicity toward mammalian cells. Synthesis of analogs provided a few inhibitors that retained antibacterial activity and demonstrated a significant reduction in cytotoxicity. The impact of serum and initial investigations toward a mode of action highlight several features of this class of compounds as antibacterials.