Antibacterial Natural Products Research Articles

4-Aminothiazolyl Analogues of GE2270 A: Antibacterial Lead Finding

4-Aminothiazolyl analogues of the antibacterial natural product GE2270 A (1) were designed, synthesized, and evaluated for gram positive bacteria growth inhibition. The aminothiazole-based chemical template was evaluated for chemical stability, and its decomposition revealed a novel, structurally simplified, des-thiazole analogue of 1. Subsequent stabilization of the 4-aminothiazolyl functional motif was achieved and initial structure activity relationships defined.

ChemInform Abstract: Antibacterials from the Sea

AbstractReview: 195 refs.

A stereoselective, Sm(ii)-mediated approach to decorated cis-hydrindanes: synthetic studies on faurinone and pleuromutilin

The cis-hydrindane motif is found in a number of natural products that display important biological activity. A flexible, stereoselective approach to the framework has been developed that features highly diastereoselective, SmI(2)-mediated cyclisations. The strategy has been exploited in the first synthesis of the proposed structure of faurinone and an approach to the skeleton of the antibacterial natural product, pleuromutilin.

Total Synthesis of (−)-Muraymycin D2 and Its Epimer

Full details of the first total synthesis of (-)-muraymycin (MRY) D2 and its epimer, the antibacterial nucleoside natural product, are described. Key strategic elements of the approach include the preparation of the urea dipeptide moiety found in the muraymycins containing an L-epi-capreomycidine via a nitrene C-H insertion of the sulfamate 10 and the fully protected muraymycin skeleton at a late stage by an Ugi four-component reaction. Thus, the nitrene C-H insertion of the sulfamate 10 with 10 mol % of Rh(2)(esp)(2) catalyst gave the cyclic sulfamates 11a and 11b in 47% yield (11a:11b = 1:2.0). Construction of the cyclic guanidine skeleton was effected through the HgBr(2)-promoted cyclization of 42 followed by desulfonylation upon acetolysis of the oxathiazinane ring to give 43 in good yield. The amine obtained by selective removal of the Cbz group of the alcohol 44 was reacted with MeSC(=O)-L-Val-O-t-Bu (38) to provide 45, which was oxidized to the carboxylic acid 46. Reaction of 46, isonitrile 51, isovaleraldehyde, and 2,4-dimethoxybenzylamine furnished the desired Ugi products, the final deprotection of which successfully afforded (-)-MRY D2 and epi-MRY D2 (53) after HPLC separation of the diastereomers. This approach would afford ready access to a range of analogues simply by altering each component.

Total Synthesis of (±)-Cordypyridones A and B and Related Epimers

Efficient racemic synthesis of two antibacterial and antimalarial natural products, cordypyridones A and B, was achieved from inexpensive, commercially available starting materials in an overall yield of 15% (8% and 7%, respectively). This convergent synthesis utilizes a key coupling step of two fragments and the subsequent functional group transformations lead to the target compounds and their 8-epi-analogues.

Stereoselective synthesis of the C1–C12 fragment of the thuggacins

A concise asymmetric synthesis of the C1–C12 fragment of the antibacterial natural product thuggacins has been achieved. The stereochemistry of this fragment was established efficiently via stereoselective reduction and Evans-aldol condensation. Hanztsch’s method and a Horner–Wadsworth–Emmnons reaction were employed for thiazole formation and the construction of the E-α,β-unsaturated double bond.

Nickel-Catalyzed Carbocyanation of Alkynes with Allyl Cyanides

Allyl cyanides are found to add across alkynes in the presence of a nickel/P(4-CF(3)-C(6)H(4))(3) catalyst to give polysubstituted 2,5-hexadienenitriles with defined stereo- and regiochemistry. Use of AlMe(2)Cl or AlMe(3) as a Lewis acid cocatalyst accelerates the reaction and expands the substrate scope significantly. The cyano group in the allylcyanation products can be transformed to a hydroxymethyl or aminomethyl group to afford highly substituted allylic alcohols or amines. Alpha-siloxyallyl cyanides also add across alkynes selectively at the less hindered gamma-carbon to allow introduction of 3-oxo-propyl functionality after hydrolysis of the resulting silyl enol ethers. This particular carbocyanation reaction has been applied to the stereoselective construction of the trisubstituted double bond of plaunotol, an antibacterial natural product active against Helicobacter pylori.

Discovery and antibacterial activity of glabramycin A–C from Neosartorya glabra by an antisense strategy

Treatment of drug-resistant bacteria is a significant unmet medical need. This challenge can be met only by the discovery and development of new antibiotics. Antisense technology is one of the newest discovery tools that provides enhanced sensitivity for detection of antibacterials, and has led to the discovery of a number of interesting new antibacterial natural products. Continued utilization of this technology led to the discovery of three new bicyclic lactones, glabramycins A-C, from a Neosartorya glabra strain. Glabramycin C showed strong antibiotic activity against Streptococcus pneumoniae (MIC 2 microg ml(-1)) and modest antibiotic activity against Staphylococcus aureus (MIC 16 microg ml(-1)). The isolation, structure, relative configuration and antibacterial activity, and plausible biogenesis of these compounds have been discussed.

DRUG DISCOVERY Lilly initiative starts up with new candidates to advance against tuberculosis

The Lilly TB Drug Discovery Initiative has opened its labs and acquired the first compounds it will develop against tuberculosis. Created in mid-2007, the Seattle-based public-private partnership includes Eli Lilly & Co.; the Infectious Disease Research Institute (IDRI), a nonprofit organization focused on diseases that inordinately affect the world’s poor populations; and NIH’s National Institute of Allergy & Infectious Diseases. The compounds are a new class of antibiotics from the British biotech firm Summit and CPZEN-45 from Tokyo-based Microbial Chemistry Research Foundation. CPZEN-45 may offer a new mechanism of action against TB and is known to be active against drug-resistant forms. The TB initiative is also beginning its main task of screening compounds against new bacterial targets. Lilly has opened its library of 500,000 compounds, and Merck & Co. is making available to the partnership libraries of antibacterial compounds and natural products. By helping to fill the early-stage drug development...

Medicinal Chemistry Targeting Nucleosides and Nucleic Acids Based on Fine Synthetic Chemistry

Nucleosides and nucleotides are one of the most important elements for cells by the fact that they are components of DNAs and RNAs. In addition, they play important roles in most fundamental cellular metabolic pathways such as energy donors, second messengers, and cofactors for various enzymes. Therefore, there exists a rich source in drug discovery targeting nucleosides and nucleotides. In order to utilize nucleosides and nucleic acids on the drug development, it is very important to develop reactions and methods, by which the highly coordinating and labile nucleoside intermediates can be used. With these in mind, we have been working on synthetic nucleoside and nucleic acid chemistry. First, branched sugar nucleoside derivatives, which are potential antitumor agents, have been synthesized utilizing samarium diiodide (SmI(2)) mediated Reformatsky reaction or aldol reaction. 3'-beta-Carbamoylmethylcytidine (CAMC) was found to exhibit potent cytotoxicity against various human tumor cell lines. Synthetic methodology of the caprazamycins, which are promising antibacterial nucleoside natural products, was also developed by the strategy including beta-selective ribosylation without using a neighboring group participation. Our synthetic route provided a range of key analogues with partial structures to define the pharmacophore. Simplification of the caprazamycins was further pursued to develop diketopiperazine analogs. Medicinal chemistry of oligodeoxynucleotides has been conducted. Thus, novel triazole-linked dumbbell oligodeoxynucleotides and modular bent oligodeoxynucleotides were synthesized. They exhibit excellent binding affinity to NF-kappaB or HMGB1 A-box protein, which are important therapeutic targets. Therefore, the results obtained conclusively demonstrated these oligodeoxynucleotides could be proposed as powerful decoy molecules.

Chemistry and Structure-Activity Relationship of Antibacterial Nucleoside Natural Products

Synthetic methodology of the caprazamycins, which are promising antibacterial nucleoside natural products, was developed. Palmitoylcaprazol, which possesses a simple fatty acyl side chain at the diazepanone moiety of caprazamycins, has been synthesized and exhibited antibacterial activity against pathogens threatening a public health. Simplification of the caprazamycins was further pursued to develop diketopiperazine analogs.

Isolation of antibacterial diterpenoids from Cryptomeria japonica bark

The aims of the present study were to determine the antibacterial activity of bark extract of Cryptomeria japonica D. Don and to isolate potential antibacterial constituents. The results showed that the ethanolic extract of C. japonica bark possessed a good antibacterial activity. Nine compounds including seven diterpenoids (ferruginol (I), isopimaric acid (II), iguestol (III), isopimarol (IV), phyllocladan-16α-ol (V), sandaracopimarinol (VI) and sugiol (VII)) and two steroids (β-sitosterol (VIII) and β-sitostenone (IX)) were isolated from active subfractions; β-sitostenone was isolated for the first time from this plant. Among these compounds, ferruginol possessed the strongest antibacterial activity and had MIC values ranging from 6.3 to 12.5 µg mL−1 against all bacteria tested. Isopimaric acid was also an antibacterial natural product. Cryptomeria japonica bark extract and its diterpenoids, ferruginol and isopimaric acid, have the ability to inhibit the bacterial growth and can be used as the source for natural bactericides.

Fine Synthetic Nucleoside Chemistry Based on Nucleoside Natural Products Synthesis

Synthetic nucleoside chemistry based on nucleoside natural products synthesis were described. First, a samarium diiodide (SmI 2)-promoted aldol reaction with the use of alpha-phenylthioketone as an enolate was developed. The characteristics of this reaction are that the enolate can be regioselectively generated and the aldol reaction proceeds under near neutral condition. This reaction is proved to be a powerful reaction for the synthesis of complex nucleoside natural products, and herbicidin B and fully protected tunicaminyluracil, which were undecose nucleoside natural products, were synthesized. Next, the synthetic methodology of the caprazamycins, which are promising antibacterial nucleoside natural products, was also developed by the strategy including beta-selective ribosylation without using a neighboring group participation. Our synthetic route provided a range of key analogues with partial structures to define the pharmacophore. Simplification of the caprazamycins was further pursued to develop diketopiperazine analogs.

Fungal endophytes from Dioscorea zingiberensis rhizomes and their antibacterial activity

The aim of the study was to isolate and characterize the endophytic fungi from the rhizomes of the Chinese traditional medicinal plant Dioscorea zingiberensis and to detect their antibacterial activities. After strict sterile sample preparation, nine fungal endophytes were isolated from rhizomes of the Chinese traditional medicinal plant D. zingiberensis. The endophytes were classified by morphological traits and internal transcribed spacer (ITS) rRNA gene sequence analysis. Their ITS rDNA sequences were 99-100% identical to Nectria, Fusarium, Rhizopycnis, Acremonium and Penicillium spp. respectively. Of these, the most frequent genera were Fusarium and Nectria. One isolate, Dzf7, was unclassified on the basis of its low sequence similarity. The next closest species was Alternaria longissima (c. 92.4% sequence similarity). Endophyte isolate Dzf5 showed the closest sequence similarity (c. 99.5%) to an uncultured soil fungus (DQ420800) obtained from Cedar Creek, USA. Bioassays using a modified broth dilution test were used to detect the antibacterial activity of n-butanol extracts of both mycelia and culture filtrates of D. zingiberensis showed biological activity against Bacillus subtilis, Staphylococcus haemolyticus, Escherichia coli and Xanthomonas vesicatoria. Minimal inhibitory concentration (MIC) values of the extracts were between 31 x 25 microg ml(-1) and 125 microg ml(-1). Endophytic fungus Dzf2 (c. 99 x 8% sequence similarity to Fusarium redolens) isolated from D. zingiberensis rhizome showed the most potent antibacterial activities. Endophytic fungi isolated from D. zingiberensis may be used as potential producers of antibacterial natural products.

Nucleoside natural products and related analogs with potential therapeutic properties as antibacterial and antiviral agents

Nucleoside natural products possess a variety of interesting biological activities, including antibacterial, antiviral and antitumor properties, and are therefore expected to be potential candidates for developing drugs. Complex nucleoside natural products exhibiting antibacterial activity by specific inhibition of bacterial cell wall peptidoglycan biosynthesis are described. In addition to the class of antibacterial nucleoside natural products, the newest members of nucleoside natural products exhibiting interesting antiviral activity are briefly described. In spite of promising properties, no nucleoside natural products and their analogs are presently used in the clinic. A global structure–activity relationship of these classes of nucleoside natural products clearly indicates that it is very important to: i) modulate the cell entry ability; and ii) simplify hydrophilic core structures in order to reduce the size of molecules and stabilize the chemically labile structure.

Antibacterial Natural Products in Medicinal Chemistry — Exodus or Revival?

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 200 leading journals. To access a ChemInform Abstract, please click on HTML or PDF.

Antibacterial Natural Products in Medicinal Chemistry—Exodus or Revival?

To create a drug, nature's blueprints often have to be improved through semisynthesis or total synthesis (chemical postevolution). Selected contributions from industrial and academic groups highlight the arduous but rewarding path from natural products to drugs. Principle modification types for natural products are discussed herein, such as decoration, substitution, and degradation. The biological, chemical, and socioeconomic environments of antibacterial research are dealt with in context. Natural products, many from soil organisms, have provided the majority of lead structures for marketed anti-infectives. Surprisingly, numerous "old" classes of antibacterial natural products have never been intensively explored by medicinal chemists. Nevertheless, research on antibacterial natural products is flagging. Apparently, the "old fashioned" natural products no longer fit into modern drug discovery. The handling of natural products is cumbersome, requiring nonstandardized workflows and extended timelines. Revisiting natural products with modern chemistry and target-finding tools from biology (reversed genomics) is one option for their revival.

Phospho-MurNAc-Pentapeptide Translocase (MraY) as a Target for Antibacterial Agents and Antibacterial Proteins

Phospho-MurNAc-pentapeptide translocase (MraY, translocase I) catalyses the first step of the lipid-linked cycle of reactions of bacterial peptidoglycan biosynthesis. MraY is the target for five families of nucleoside antibacterial natural products: the tunicamycins, the mureidomycins (also pacidamycins, napsamycins), the liposidomycins, the muraymycins, and the capuramycins. Recent structure-activity studies on these families have led to the identification of active pharmacophores, and insight into their mechanisms of action. This step of peptidoglycan biosynthesis is also the target for the bacteriolytic E protein from bacteriophage phiX174, and for cyclic peptides of the amphomycin family which complex the undecaprenyl phosphate co-substrate. The mechanisms of enzyme inhibition by these agents are discussed, and the state of knowledge regarding the transmembrane structure, active site, and catalytic mechanism of MraY. The availability of high throughput assays and prospects of MraY as an antibacterial target are also discussed.

A Diels–Alder Macrocyclization Enables an Efficient Asymmetric Synthesis of the Antibacterial Natural Product Abyssomicin C

A Diels–Alder Macrocyclization Enables an Efficient Asymmetric Synthesis of the Antibacterial Natural Product Abyssomicin C

A Diels–Alder Macrocyclization Enables an Efficient Asymmetric Synthesis of the Antibacterial Natural Product Abyssomicin C

A Diels–Alder Macrocyclization Enables an Efficient Asymmetric Synthesis of the Antibacterial Natural Product Abyssomicin C