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.     

Rifamycin antibiotics—new compounds and synthetic methods. Part 1: Study of the reaction of 3-formylrifamycin SV with primary alkylamines or ammonia

Within the study covering the search for new methods of synthesis of rifamycin antibiotics, the reactions of 3-formylrifamycin SV (2) with primary amines or ammonia were studied. In the reaction of 2 with methylamine, unstable 3-methyliminomethylrifamycin SV (8) was formed, which was further oxidised to stable 3-methyliminomethylrifamycin S (9). In the reaction of 2 with ammonia, N,15-didehydro-15-deoxo-pyrimido-(4,5-b)rifamycin SV (10), a new compound with a chromophore system enlarged by a pyrimidine ring, was obtained. The product of its reduction with sodium borohydride—(11)—was also isolated. The structures of the compounds and an explanation of the synthesis mechanism have been proposed on the basis of mass spectrometry results as well as (1D) and (2D) ¹H- and ¹³C NMR analysis. In vitro antituberculous activity of the new compounds have been investigated.     

13C and 15N CP/MAS, 1H–15N SCT CP/MAS and FTIR spectroscopy as tools for qualitative detection of the presence of zwitterionic and non‐ionic forms of ansa‐macrolide 3‐formylrifamycin SV and its derivatives in solid state

¹³C, ¹⁵N CP/MAS, including ¹H–¹³C and ¹H–¹⁵N short contact time CP/MAS experiments, and FTIR methods were applied for detailed structural characterization of ansa‐macrolides as 3‐formylrifamycin SV (1) and its derivatives (2–6) in crystal and in powder forms. Although HPLC chromatograms for 2/CH₃OH and 2/CH₃CCl₃ were the same for rifampicin crystals dissolved in respective solvents, the UV–vis data recorded for them were different in 300–375 nm region. Detailed solid state ¹³C and ¹⁵N CP/MAS NMR and FTIR studies revealed that rifampicin (2), in contrast to 3‐formylrifamycin SV (1) and its amino derivatives (3–6), can occur in pure non‐ionic or zwitterionic forms in crystal and in pure these forms or a mixture of them in a powder. Multinuclear CP/MAS and FTIR studies demonstrated also that 3–6 derivatives were present exclusively in pure zwitterionic forms, both in powder and in crystal. On the basis of the solid state NMR and FTIR studies, two conformers of 3‐formylrifamycin SV were detected in powder form due to the different orientations of carbonyl group of amide moiety. The PM6 molecular modeling at the semi‐empirical level of theory, allowed visualization the most energetically favorable non‐ionic and zwitterionic forms of 1–6 antibiotics, strongly stabilized via intramolecular H‐bonds. FTIR studies indicated that the originally adopted forms of these type antibiotics in crystal or in powder are stable in standard laboratory conditions in time. The results presented point to the fact that because of a possible presence of two forms of rifampicin (compound 2), quantification of the content of this antibiotic in relevant pharmaceuticals needs caution. Copyright © 2013 John Wiley & Sons, Ltd.     

The influence of pH and anions on the adsorption mechanism of rifampicin on silver colloids

The influence of pH and anions on the adsorption mechanism of rifampicin on colloidal silver nanoparticles has been analysed by electronic absorption, resonance Raman (RR) and surface‐enhanced resonance Raman spectroscopy (SERRS). Rifampicin is a widely used antibiotic with a zwitterionic nature. SERRS spectra of rifampicin adsorbed on silver sols, prepared using hydroxylamine hydrochloride as reducing agent, undergo dramatic changes upon lowering the pH. The spectral form changes progressively from that characteristic of chemisorbed rifampicin (at pH > 7) to one very similar to the rifampicin RR spectrum (at lower pH), indicative of a modification of the adsorption mechanism on the surface of the Ag nanoparticles. The RR‐type SERRS spectrum is proposed to result from formation of an ion pair between rifampicin and Cl⁻ anions, which, deriving from the colloid preparation, are adsorbed on the Ag surface. The addition of anions to the hydroxylamine hydrochloride sol facilitates conversion from the chemisorbed to ion pair form and leads to an order of magnitude increase in the SERRS signal. Copyright © 2007 John Wiley & Sons, Ltd.     

Regioselective Long‐Range Proton Transfer in New Rifamycin Antibiotics: A Process in which Crown Ethers Act as Stronger Brønsted Bases than Amines

Water‐mediated proton transfer in six new derivatives of 3‐formylrifamycin SV that contain crown, aza‐crown, and benzo‐crown ether rings were investigated by FTIR and NMR spectroscopy. ¹H–¹H COSY couplings provide evidence for the formation of zwitterionic structures of the aza‐crown and crown ether derivatives of rifamycin, in which a proton from one of the phenolic groups is transferred to tertiary and secondary nitrogen atoms. The increased intensity of the continuous absorption in the mid‐infrared region together with the NMR data indicate proton transfer from the phenol group of the rifamycin core to the cavity of the benzo‐crown ether ring. This proton transfer is achieved by formation of hydronium (H₃O⁺) or Zundel ions (H₅O₂⁺), which form intermolecular hydrogen bonds with the oxygen atoms of the crown ether. DFT calculations are in agreement with the spectroscopic data and allow visualization of the structures of all new rifamycin derivatives, characterized by different intramolecular protonation sites.