Contributions to the synthesis of some ferrocene-containing antibiotics

This Review discusses the synthesis and characterization by our Group of new antibiotics belonging to the class of penicillins, cephalosporins and rifamycins with ferrocenyl and 1, 1′-ferrocenilene residues in the molecule. As reactants for 6-aminopenicillanic acid (6-APA) and 7-aminocephalosporanic acid (7-ACA) the following were used: 1, 1-bis(chlorocarbonyl)ferrocene, ferrocenyl sulfochloride, 1, 1′-ferrocenylenedisulfochloride and thioglycolic acids S-modified with ferrocene. In the synthesis of rifamycins, the hydrazides of the thioglycolic acids, S-modified with ferrocene, were employed as nucleophilic agents. The synthesized intermediates were characterized by elemental analysis, TLC, IR, UV and ¹H NMR spectra. The characterization of new antibiotics was made by TLC, IR and UV spectral analysis. Biological activity was tested on Gram-negative and Gram-positive bacteria. Good activity is reported towards Gram-positive bacteria in the case of derivatives containing residues of thioglycolic acid S-modified with ferrocene, the antibacterial activity being similar to that of amoxicillin, carbenicillin and cephalothin. All compounds are inactive towards Gram-negative bacteria.     

Vancomycin Analogues Containing Monosaccharides Exhibit Improved Antibiotic Activity: A Combined One‐Pot Enzymatic Glycosylation and Chemical Diversification Strategy

Many natural products contain carbohydrate moieties that contribute to their biological activity. Manipulation of the carbohydrate domain of natural products through multiple glycosylations to identify new derivatives with novel biological activities has been a difficult and impractical process. We report a practical one‐pot enzymatic approach with regeneration of cosubstrates to synthesize analogues of vancomycin that contain an N‐alkyl glucosamine, which exhibited marked improvement in antibiotic activity against a vancomycin‐resistant strain of Enterococcus.     

Solid-phase synthesis of dihydrovirginiamycin S1, a streptogramin B antibiotic

We describe the first solid-phase synthesis of dihydrovirginiamycin S(1), a member of the streptogramin B family of antibiotics, which are nonribosomal-peptide natural products produced by Streptomyces. These compounds, along with the synergistic group A components, are "last line of defense" antimicrobial agents for the treatment of life-threatening infections such as vancomycin-resistant enterococci. The synthesis features an on-resin cyclization and is designed to allow production of streptogramin B analogues with diversification at positions 1', 1, 2, 3, 4, and 6. Several synthetic challenges known to hinder the synthesis of this class of compounds were solved, including sensitivity to acids and bases, and epimerization and rearrangements, through the judicious choice of deprotection conditions, coupling conditions, and synthetic strategy. This work should enable a better understanding of structure-activity relationships in the streptogramin B compounds, possible identification of analogues that bypass known resistance mechanisms, and perhaps the identification of analogues with novel biological activities.     

Formal synthesis of tubelactomicins via a transannular Diels-Alder approach

A formal synthesis of the antimicrobial tricyclic macrolides, tubelactomicins A and E, featured by a transannular Diels-Alder (TADA) approach, has been explored. The key issue for the transannular cyclization was the synthesis of a 24-membered macrolactone equipped with all the requisite functionalities, which has been achieved using an intramolecular Hiyama cross-coupling strategy. The Hiyama coupling reaction spontaneously triggered off the TADA reaction. From the endo-TADA adduct, formal syntheses of tubelactomicins A and E were achieved. The 24-membered macrolactone formation was also achieved via an intramolecular ring-closing metathesis approach.     

Electrode Kinetics and Ternary Complex Formation of Cd2+‐Antibiotics‐Vitamin‐B5 System. A Polarographic Study

Cd²⁺ complexes with antibiotics viz. neomycin, chlortetracycline, oxytetracycline, tetracycline, penicillin‐V and penicillin‐G as primary ligands and vitamin‐B₅ as secondary ligand have been reported at pH = 7.30 ± 0.01 and μ = 1.0 M KNO₃ at 298 K by polarographic technique.¹ Cd²⁺ formed 1:1:1, 1:1:2, and 1:2:1 complexes with a stability constants trend of neomycin < chlortetracycline < oxytetracycline < tetracycline < penicillin‐V < penicillin‐G can be explained on the basis of the nature of ligands, bonding, and steric hindrance of these drugs. The nature of electrode processes were reversible and diffusion controlled. The values of stability constants showed that these drugs can be used to reduce the toxicity of Cd.     

Simultaneous Determination of Oxytetra- cycline, Doxycycline, Tetracycline and Chlortetracycline in Tetracycline Antibiotics by High-Performance Liquid Chromatog- raphy with Fluorescence Detection

A simple, rapid and sensitive high-performance liquid chromatographic method with fluorescence detection for the simultaneous determination of oxytetracycline, doxycycline, tetracycline and chlortetracycline was developed, and successfully applied to the analysis of commercial tetracycline antibiotics. The separation was performed on a reverse-phase C₁₈ column with a gradient elution composed of methanol and sodium acetate buffer (containing disodium ethylenediaminetetraacetate and calcium chloride, pH 8.10) as the mobile phase, and fluorescence detection at 532 nm (excitation at 380 nm). The detection limits for oxytetracycline, doxycycline, tetracycline and chlortetracycline were 0.1, 0.5, 0.3 and 0.4 g L^–1, respectively. Data with respect to precision and accuracy were reported and discussed.     

Reversed-phase liquid chromatographic method for the analysis of aminoglycoside antibiotics using pre-column derivatization with phenylisocyanate

A pre-column derivatization liquid chromatographic method has been developed for the analysis of aminoglycoside antibiotics using phenylisocyanate as a derivatization reagent. Derivatives including kanamycin, neomycin and gentamicin were formed by reaction of the analytes with phenylisocyanate in the presence of triethylamine. Phenylisocyanato groups were attached to corresponding amino groups of aminoglycoside and their molecular mass was confirmed by liquid chromatography-electrospray ionization-mass spectrometry (LC-ESI-MS). The experimental conditions for derivatization and separation of aminoglycoside derivatives were optimized and validated. A simple liquid chromatographic method for the determination of aminoglycoside antibiotics was demonstrated.     

Determination of macrolide antibiotics by liquid chromatography

The liquid chromatographic separation of seven macrolides used in food producing animals in the European Union has been studied. Separation was performed by using an end-capped high-purity silica-based C₁₈ column and mobile phases consisting of phosphate buffer (pH 2.5)–acetonitrile mixtures. The effect of pH and acetonitrile percentage on the separation was examined. Two UV-based detection systems, wavelength programming and diode array, were assayed. Detection limits were in the range 6–33 μg l⁻¹ for spiramycin, tilmicosin, tylosin, kitasamicin and josamicin and about 400 μg l⁻¹ for erythromycin and oleandomycin. The suitability of the method for multiresidue determination of the five macrolides is demonstrated by the analysis of spiked samples of chicken muscle.     

Highly conformationally constrained halogenated 6-spiroepoxypenicillins as probes for the bioactive side-chain conformation of benzylpenicillin

Summary The halogenated 6-spiroepoxypenicillins are a series of novel semisynthetic-lactam compounds with highly conformationally restricted side chains incorporating an epoxide. Their biological activity profiles depend crucially on the configuration at position C-3 of that epoxide. In derivatives with aromatic-containing side chains, e.g., anilide, the 3R-compounds possess notable Gram-positive antibacterial activity and potent-lactamase inhibitory properties. The comparable 3S-compounds are antibacterially inactive, but retain-lactamase inhibitory activity.Using the molecular simulation programs COSMIC and ASTRAL, we attempted to map a putative, lipophilic accessory binding site on the PBPs that must interact with the side-chain aromatic residue. Comparative computer-assisted modelling of the 3R, and 3S-anilides, along with benzylpenicillin, indicated that the available conformational space at room temperature for the side chains of the 3R and the 3S-anilides was mutually exclusive. The conformational space for the more flexible benzylpenicillin could accommodate the side chains ofboth the constrained penicillin derivatives. By a combination of van der Waals surface calculations and a pharmacophoric distance approach, closely coincident conformers of the 3R-anilide and benzylpenicillin were identified. These conformers must be related to the antibacterial, bioactive conformer for the classical-lactam antibiotics. From these proposed bioactive conformations, a model for the binding of benzylpenicillin to the PBPs relating the three-dimensional arrangement of a putative lipophilic S₂-subsite, specific for the side-chain aromatic moiety, and the 3-carboxylate functionality is presented.This work has been reported in preliminary form at the 4th Royal Society of Chemistry International Symposium on Recent Advances in the Chemistry of-lactam Antibiotics, Churchill College, Cambridge, U.K., 3–6 July 1988.     

Synthetic studies on macrolactin A by using a (diene)Fe(CO)3 complex

The stereoselective synthesis of the two segments 3 and 4 of macrolactin A 1 is described. Macrolactin A is a 24-membered polyene macrolide antibiotic, which is of interest due to a strong activity against B16-F10 murine tumor cell and HIV-1 virus. The key step of the synthesis is the 1,2-migration reaction of a (diene)Fe(CO)₃ complex with a introduction of the thiol group to construct the unstable (E,Z)-conjugated dienic moiety (C8-C11).