Identification of 2-aminothiazoyl piperidine derivatives as a new class of adjuvants potentiating the activity of colistin against Acinetobacter baumannii

The rapid prevalence of antibiotic resistance has led to a significant global health problem. Although colistin is the last resort antibiotic, it is limited by dose dependent toxicity. A critical approach to solve this problem is to use an antibiotic adjuvant, which is able to potentiate the activity of antibiotic and reduce the dosage of antibiotic. Herein, we reported a novel 2-aminothiazoyl piperidine adjuvant, which enhanced the activity of colistin against Acinetobacter baumannii (A. baumannii). Two pilot libraries of 40 compounds were prepared and their adjuvant activities were evaluated. The most potential compound 11j enabled to cause16-fold reduction in the minimum inhibitory concentration (MIC) of colistin at 8 µg/mL. Besides, time-kill curves exhibited that compound 11j had significant adjuvant activity to kill the bacteria. The predicted ADMET analysis showed that 2-aminothiazoyl piperidine derivatives had good drug-likeness and acceptable physicochemical properties. Furthermore, membrane permeability experiments demonstrated that compound 11j was beneficial for colistin to destroy the outer membrane of bacteria. Also, the comparative molecular similarity indices analysis (CoMSIA) and the density functional theory (DFT) calculations were conducted. The results drawn from these analyses indicated that the novel scaffold provided helpful information for the finding of new adjuvant lead.     

Oligoglycol carbonate prodrugs of 5-modified 2'-deoxyuridines: synthesis and antibacterial activity

In order to develop a new generation of antibacterial nucleosides, a representative set of novel 3'- and 5'-tri- or tetraethylene glycol prodrug forms of 5-alkyloxymethyl-2'- deoxyuridines was synthesized. These compounds were at least two orders of magnitude more soluble than the parent nucleosides, possessed significant inhibitory activity against a set of bacteria including resistant strains of Staphylococcus aureus and Mycobacterium smegmatis, and showed low cytotoxicity. The obtained data indicate that glycol carbonates are convenient and prospective for usage in prodrugs of nucleoside derivatives with antibacterial activity.     

Engineered hyperstructures based on attaching macromers onto polymers

The combination of polymers with macromers derived from inorganic species and oligomers to yield controlled hyperstructures can potentially allow the design of materials with tunable mechanical, optoelectronic properties and chemical behavior. In this work, novel hybrid structures were processed based upon the controlled insertion of macromers derived from inorganic groups and oligomers into previously chemically modified polymer frameworks. The chemical procedure involved a series of steps that started with the creation of a functionalized framework to act as host for the construction of the polymer-macromer hyperstructures. The designed polymer framework was obtained by incorporating highly polar groups, such as sulfonic acid, into poly(aryl ether sulfones). Following this step, the newly promoted reactive sites were used to insert alkoxysilane groups through reacting modified poly(aryl ether sulfones) with specifically selected silane compounds. The chemical reactions and the obtained novel structures were characterized using NMR, FTIR, AFM and thermal analysis. Results showed that structural parameters such as the concentration of siloxane bonds across the material and the density of cross-links could be controlled by selecting different conditions of reaction. Completely homogeneous and also heterogeneous, but still controlled, structures could be produced using the described procedure. The developed polymer structures containing controlled profiles of concentration, densities and chemical functionalities can have tailorable mechanical properties and chemical activity.     

含二茂铁的β-内酰胺的研究进展

β-内酰胺类抗生素是目前最具应用价值的抗生素, 其结构特征具有β-内酰胺环的基元结构, 该类化合物的设计、合成和立体化学研究一直是有机合成化学研究的前沿和热点领域. 二茂铁凭借其独特的结构和多样的性质, 在生物和医药方面均有广泛的应用价值. 因此, 二茂铁修饰的β-内酰胺是一类结构新颖且具有潜在生物活性的化合物. 对该类化合物的深入研究, 将对新型抗生素的研发提供重要的指导意义. 综述了近年来青霉烷类和头孢烯类β-内酰胺及单环类β-内酰胺这两大类含二茂铁取代的β-内酰胺衍生物的合成与生物活性的研究进展.     

Parviflorenes B-F, novel cytotoxic unsymmetrical sesquiterpene-dimers with three backbone skeletons from Curcuma parviflora

Five novel natural products classified as dimeric sesquiterpenes, named parviflorenes B-F (2-6), possessing three types of novel backbone frameworks, have been isolated from Curcuma parviflora (Zingiberaceae). The structures of 2-6 were elucidated by means of spectroscopic studies, and the structure of 2 was further unambiguously established by X-ray crystallographic analysis. Compounds 2, 4, and 6 have an unsymmetrical bis-cadinane skeleton, while compound 3 is a dimer of cadinane and iso-cadinane, and compound 5 possesses another novel carbon framework consisting of two cadinanes with different bond-connection. These new compounds with novel carbon skeletons showed cytotoxicity against tumor cell lines.     

The effect of a sulphur bridge on the photochromic properties of indeno-fused naphthopyrans

The synthesis of four new 2,2-diphenyl-2H-naphtho[1,2-b]pyrans with a fused indeno group at the f face and a sulphur junction between the 2,2-phenyl groups is described. The photochromic properties in solution of these novel compounds were investigated under continuous irradiation. Compared to known indeno-fused naphthopyrans, these new compounds showed a significant bathochromic shift in the spectra of the open forms, faster ring closure kinetics and an expected decrease in the colourabilities.     

Lanthanide co-ordination frameworks: Opportunities and diversity

Significant successes have been made over recent years in preparing co-ordination framework polymers that show macroscopic material properties, but in the vast majority of cases this has been achieved with d-block metal-based systems. Lanthanide co-ordination frameworks also offer attractive properties in terms of their potential applications as luminescent, non-linear optical and porous materials. However, lanthanide-based systems have been far less studied to date than their d-block counterparts. One possible reason for this is that the co-ordination spheres of lanthanide cations are more difficult to control and, in the absence of design strategies for lanthanide co-ordination frameworks, it is significantly more difficult to target materials with specific properties. However, this article highlights some of the exciting possibilities that have emerged from the earliest investigations in this field with new topological families of compounds being discovered from relatively simple framework components, including unusual eight, seven and five-connected framework systems. Our own research, as well as others, is leading to a much greater appreciation of the factors that control framework formation and the resultant observed topologies of these polymers. As this understanding develops targeting particular framework types will become more straightforward and the development of designed polyfunctional materials more accessible. Thus, it can be seen that lanthanide co-ordination frameworks have the potential to open up previously unexplored directions for materials chemistry. This article focuses on the underlying concepts for the construction of these enticing and potentially highly important materials.     

A β-cyclodextrin covalent organic framework used as a chiral stationary phase for chiral separation in gas chromatography

Chiral covalent organic frameworks(CCOFs) featuring chirality, stability, and good porosity have attracted a considerable amount of attention due to their important applications, such as asymmetric catalysis, chiral separation, and chiral recognition. In this study, a β-cyclodextrin(β-CD) covalent organic framework(β-CD-COF) diluted with polysiloxane OV-1701 was explored as a novel chiral stationary phase(CSP) for gas chromatography(GC) separation of racemates. The β-CD-COF coated capillary colu...     

Isolation and characterization of miscellaneous terpenoids of Schisandra chinensis

Two new bisnortriterpenoids with 18-norschiartane skeleton, wuweizidilactones G (1) and H (2), four new highly oxygenated nortriterpenoids based on a schisanartane skeleton, schindilactones D-G (3-6), a pre-schisanartane skeleton, pre-schisanartanin B (7), and a novel 3,4-seco-21,26-olide-artane triterpenoid wuweizilactone acid (8), along with 24 known terpenoids with different carbon frameworks, have been isolated from the acetone extract of the stems and leaves of Schisandra chinensis. The terpenoids produced by this plant have chemical diversity. The structures of new compounds 1-8 have been characterized by spectroscopic data interpretation. The cytotoxicity and anti-HIV-1 activity of all the Schisandra nortriterpenoids were evaluated.     

Strong Antibiotic Activity of the Myxocoumarin Scaffold in vitro and in vivo

The increasing emergence of resistances against established antibiotics is a substantial threat to human health. The discovery of new compounds with potent antibiotic activity is thus of utmost importance. Within this work, we identify strong antibiotic activity of the natural product myxocoumarin B from Stigmatella aurantiaca MYX-030 against a range of clinically relevant bacterial pathogens, including clinical isolates of MRSA. A focused library of structural analogs was synthesized to explore initial structure-activity relationships and to identify equipotent myxocoumarin derivatives devoid of the natural nitro substituent to significantly streamline synthetic access. The cytotoxicity of the myxocoumarins as well as their potential to cure bacterial infections in vivo was established using a zebrafish model system. Our results reveal the exceptional antibiotic activity of the myxocoumarin scaffold and hence its potential for the development of novel antibiotics.     

A chiral SrSi2 (srs) superstructure constructed by a dual interaction system showing isotropic electrical conductivity

Most porous conductive frameworks are highly anisotropic in their structures thus leading to anisotropic charge transport. Here we report a supramolecular self-assembly which is constructed by intermolecular hydrogen bonding and π ···π interactions. This material features a chiral, porous, cubic framework structure with π-stacked helical columns along all of the three Cartesian coordinates. As a result, isotropic charge transport with an electrical conductivity(σ) of 2.1 × 10^–7S/cm is...     

Synthesis of new chiral fluorescent sensors and their applications in enantioselective discrimination

Five novel sensors (R,R)-3–6 and (S, S)-6 were synthesized and developed for enantioselective recognition of chiral compounds. Sensor 6 with two thiourea groups and steric π-conjugation frameworks could discriminate different chiral substrates, including acidic compounds, basic compounds, and neutral compounds. These results disclosed that the outstanding performance of enantioselective discrimination could be attributed to the thiourea group which acted as a hydrogen-bonding donor and the bulky steric moiety of the hosts which provided appropriate chiral environment. This result will be of great practical value in the designation of chiral sensors and high-throughput assay of chiral products.     

Naturally occurring antitubercular cyclic peptides

The antibiotic pipeline has failed to keep pace with the rise of multidrug resistant tuberculosis and extensively drug-resistant tuberculosis pathogens. Naturally occurring peptides provide a rich source of lead compounds for developing novel pharmaceuticals with high selectivity and potency. Given the vast number of naturally-occurring bioactive cyclic peptides identified so far, the following digest highlights several cyclic peptides, discovered in the preceding decade, that exhibit promising activity against Mycobacterium tuberculosis.     

Isomerization of cyclobutane ligands in the solid state and solution

Cyclobutane compounds are a class of compounds that can be conveniently synthesized in the solid state by employing crystal engineering principles. The rctt-isomer (or the syn-dimer) is the most common form of any cyclobutene compound that is obtained in the solid state by the photochemical [2 + 2] cycloaddition reactions. However, these rctt-isomers can be converted to other less accessible forms, under some special conditions. Isomerization of cyclobutane compounds thus plays an important role in synthetic chemistry. Such isomerization of cyclobutane compounds have been reported in organic salts, metal complexes, coordination polymers and metal-organic frameworks. In this review, these fascinating examples of isomerization that occur both in the solid state and solution phase have been discussed.     

Isolation, enzyme-bound structure, and activity of platensimycin A1 from Streptomyces platensis

Inhibition of fatty acid synthesis is emerging as a valuable target for antibacterial agents. Platensimycin and platencin are novel natural products that were reported recently to inhibit the FabF and FabF/FabH condensing enzymes, respectively, present in the fatty acid biosynthetic pathway. Selective inhibition of these enzymes by platensimycin and platencin accounts for their potent antibiotic activity. We have continued our quest to find additional members of this class of compounds leading to discovery of platensimycin A₁, a hydroxylated congener. We report herein the isolation, structure, antibacterial and enzymatic activities, and co-crystal structure bound to Escherichia coli FabF. The lower activity of platensimycin A₁ suggests that substitution at C-14 is detrimental for the activity.     

Bioactive terpenoids from caribbean marine algae of the genera penicillus and udotea (chlorophyta)

Chemical examinations of the Caribbean green algal genera Penicillus Lamarck and Udotea Lamouroux (Family Udoteaceae, Order Caulerpales, Phylum Chlorophyta) have resulted in the isolation of six new linear terpenoid compounds from two major species of Penicillus, and six terpenoid metabolites from three species of Udotea. These new metabolites possess a wide range of antibiotic activity, some produce inhibition of cell division in the fertilized urchin egg bioassay, and several show toxicity toward herbivorous damselfish.     

Densely Functionalized 2-Methylideneazetidines: Evaluation as Antibacterials

Twenty-two novel, variously substituted nitroazetidines were designed as both sulfonamide and urethane vinylogs possibly endowed with antimicrobial activity. The compounds under study were obtained following a general procedure recently developed, starting from 4-nitropentadienoates deriving from a common β-nitrothiophenic precursor. While being devoid of any activity against fungi and Gram-negative bacteria, most of the title compounds performed as potent antibacterial agents on Gram-positive bacteria (E. faecalis and three strains of S. aureus), with the most potent congener being the 1-(4-chlorobenzyl)-3-nitro-4-(p-tolyl)azetidine 22, which displayed potency close to that of norfloxacin, the reference antibiotic (minimum inhibitory concentration values 4 and 1–2 μg/mL, respectively). Since 22 combines a relatively efficient activity against Gram-positive bacteria and a cytotoxicity on eucharyotic cells only at 4-times higher concentrations (inhibiting concentration on 50% of the cultured eukaryotic cells: 36 ± 10 μM, MIC: 8.6 μM), it may be considered as a promising hit compound for the development of a new series of antibacterials selectively active on Gram-positive pathogens. The relatively concise synthetic route described herein, based on widely available starting materials, could feed further structure–activity relationship studies, thus allowing for the fine investigation and optimization of the toxico-pharmacological profile.     

Excellent treatment activity of biscoumarins and dihydropyrans against P. aeruginosa pneumonia and reinforcement learning for designing novel inhibitors

Pseudomonas aeruginosa (P. aeruginosa) is a common clinical pathogen, which can easily cause cystic fibrosis and even bacteremia. In recent years, the antibiotic resistance of P. aeruginosa has been increasing. In an attempt to develop novel antibacterial agents, a series of biscoumarins (1–5) and dihydropyrans (6–10) were successfully prepared. The molecular structures of two representative compounds, that is, 1 and 6 were confirmed by single crystal X-ray diffraction study. The anti-bacterial activity of these synthesized compounds in vitro was evaluated by measuring the MIC values, as well as the P. aeruginosa growth curves. Next, the in vivo treatment activity of these compounds against the P. aeruginosa pneumonia infection was assessed by observing the survival rate of the infected mice and counting the bacterial load with colony plate counting assay. Additionally, the ELISA detection was conducted to evaluate the inflammatory response levels by measuring the IL-1β and TNF-α content released into the plasma, nasal lavage fluid and alveolar lavage fluid. The HE staining was also carried out to detect the protective effect of the compounds on the lung tissue damage. Further, novel anti-bacterial structures that are based on biscoumarin 5 are predicted and evaluated using reinforcement learning technic, and two outstanding pharmaceutical structures with low binding energy and high SA and QED scores are analyzed in detail using molecular docking simulation.     

Enhancement of Antibiotic Activity by 1,8-Naphthyridine Derivatives against Multi-Resistant Bacterial Strains

The search for new antibacterial agents has become urgent due to the exponential growth of bacterial resistance to antibiotics. Nitrogen-containing heterocycles such as 1,8-naphthyridine derivatives have been shown to have excellent antimicrobial properties. Therefore, the purpose of this study was to evaluate the antibacterial and antibiotic-modulating activities of 1,8-naphthyridine derivatives against multi-resistant bacterial strains. The broth microdilution method was used to determine the minimum inhibitory concentration (MIC) of the following compounds: 7-acetamido-1,8-naphthyridin-4(1H)-one and 3-trifluoromethyl-N-(5-chloro-1,8-naphthyridin-2-yl)-benzenesulfonamide. The antibiotic-modulating activity was analyzed using subinhibitory concentrations (MIC/8) of these compounds in combination with norfloxacin, ofloxacin, and lomefloxacin. Multi-resistant strains of Escherichia coli, Pseudomonas aeruginosa, and Staphylococcus aureus were used in both tests. Although the compounds had no direct antibacterial activity (MIC ≥ 1.024 µg/mL), they could decrease the MIC of these fluoroquinolones, indicating synergism was obtained from the association of the compounds. These results suggest the existence of a structure–activity relationship in this group of compounds with regard to the modulation of antibiotic activity. Therefore, we conclude that 1,8-naphthyridine derivatives potentiate the activity of fluoroquinolone antibiotics against multi-resistant bacterial strains, and thereby interesting candidates for the development of drugs against bacterial infections caused by multidrug resistant strains.