A series of eleven cymantrene-and cyrhetrene-nucleobase conjugates together with the hitherto unreported N7-isomer of the ferrocene-adenine conjugate have been synthesised and characterized. The synthetic approach involved a Michael addition reaction of in situ generated acryloylcymantrene, acryloylcyrhetrene and acryloylferrocene with canonical nucleobases, such as thymine, uracil and adenine, respectively. The mechanism of these reactions was investigated by means of density functional theory (DFT) calculations.The respective products were characterized by spectroscopic methods and by electrochemical measurements. The molecular structure of one cymantrene-adenine conjugate (5) in the solid state was determined by single-crystal X-ray structure analysis, confirming the N9-substitution mode of the adenine moiety. It was found that the molecule adopts a bent conformation with the adenine and cyclopentadienyl planes in almost perpendicular orientation. The cymantrenyl nucleobases showed an irreversible redox behaviour which is associated with ligand exchange reactions of the radical cationic species. The newly synthesised compounds were also tested for their activity against the protozoan parasite Trypanosoma brucei and human myeloid leukaemia HL-60 cells. Some compounds showed promising antitrypanosomal activity while most of them were non-toxic to HL-60 cells. It was additionally found that cymantrene and cyrhetrene ketone nucleobases were more active than their alcohol congeners. These findings indicate the potential of cymantrene and cyrhetrene nucleobase conjugates as possible lead compounds for future antitrypanosomal drug development.
The global spread of the severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) has called for an urgent need for dedicated antiviral therapeutics. Metal complexes are commonly underrepresented in compound libraries that are used for screening in drug discovery campaigns, however, there is growing evidence for their role in medicinal chemistry. Based on previous results, we have selected more than 100 structurally diverse metal complexes for profiling as inhibitors of two relevant SARS‐CoV‐2 replication mechanisms, namely the interaction of the spike (S) protein with the ACE2 receptor and the papain‐like protease PL pro . In addition to many well‐established types of mononuclear experimental metallodrugs, the pool of compounds tested was extended to approved metal‐based therapeutics such as silver sulfadiazine and thiomersal, as well as polyoxometalates (POMs). Among the mononuclear metal complexes, only a small number of active inhibitors of the S/ACE2 interaction was identified, with titanocene dichloride as the only strong inhibitor. However, among the gold and silver containing complexes many turned out to be very potent inhibitors of PL pro activity. Highly promising activity against both targets was noted for many POMs. Selected complexes were evaluated in antiviral SARS‐CoV‐2 assays confirming activity for gold complexes with N‐heterocyclic carbene (NHC) or dithiocarbamato ligands, a silver NHC complex, titanocene dichloride as well as a POM compound. These studies might provide starting points for the design of metal‐based SARS‐CoV‐2 antiviral agents.
Three gold(I) complexes of alkynyl chromones were synthesized and characterized. The single-crystal X-ray structure analysis of a dinuclear compound and of a flavone derivative exhibit a typical d 10 gold(I)-alkynyl linear arrangement. All complexes were evaluated as anticancer and antibacterial agents against four human cancer cell lines and four pathogenic bacterial strains. All compounds show antiproliferative activity at lower micromolar range concentrations. Complex 4 showed a broad activity profile, being more active than the reference drug auranofin against HepG2, MCF-7 and CCRF-CEM cancer cells. The cellular uptake into MCF-7 cells of the investigated complexes was measured by atomic absorption spectroscopy (AAS). These measurements showed a positive correlation between an increased cellular gold content and the incubation time of the complexes. Unexpectedly an opposite effect was observed for the most active compound. Biological assays revealed various molecular mechanisms for these compounds, comprising: (i) thioredoxin reductase (TrxR) inhibition, (ii) caspases-9 and -3 activation; (iii) DNA damaging activity and (iv) cell cycle disturbance. The gold(I) complexes were also bactericidal against Gram-positive methicillin-sensitive Staphylococcus aureus (MSSA) and methicillin-resistant S. aureus (MRSA) bacterial strains, while showing no activity against the Gram-negative Escherichia coli bacterial strain.
A series of six novel metallocenyl-7-ADCA (metallocenyl = ferrocenyl or ruthenocenyl; 7-ADCA = 7-aminodesacetoxycephalosporanic acid) conjugates were synthesized and their antibacterial properties evaluated by biochemical and microbiological assays. The ruthenocene derivatives showed a higher level of inhibition of DD-carboxypeptidase 64-575, a Penicillin Binding Protein (PBP), than the ferrocene derivatives and the reference compound penicillin G. Protein X-ray crystallographic analysis revealed a covalent acyl-enzyme complex of a ruthenocenyl compound with CTX-M β-lactamase E166A mutant, corresponding to a similar complex with PBPs responsible for the bactericidal activities of these compounds. Most interestingly, an intact compound was captured at the crystal-packing interface, elucidating for the first time the structure of a metallocenyl β-lactam compound that previously eluded small molecule crystallography. We propose that protein crystals, even from biologically unrelated molecules, can be utilized to determine structures of small molecules.
Recent developments in the field of organometalated antibacterial drugs and metal-based materials with antibacterial activity are reviewed. They emerge as attractive candidates for combating pathogenic bacteria including drug resistant strains.
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