Gold complexes have al ong tradition in medicine and for many examples antirheumatic, anticancer or anti-infective effectsh ave been confirmed. Herein,w e evaluated the lead compound Auranofin and five selected gold organometallics as inhibitors of two relevant drug targetso fs evere acute respiratory syndrome coronaviruses (SARS-CoV). The gold metallodrugsw ere effectivei nhibitorso ft he interaction of the SARS-CoV-2 spike protein with the angiotensin converting enzyme 2(ACE2) host receptor and might thusi nterfere with the viral entry process. The gold metallodrugsw ere also efficient inhibitors of the papain-like protease (PLpro) of SARS-CoV-1 and SARS-CoV-2, which is ak ey enzymei nt he viral replication. Regarding PLpro from SARS-CoV-2,t he here reportedi nhibitorsa re among the very first experimentally confirmed examples with activity against this target enzyme. Importantly,t he activity of the complexes against both PLpro enzymes correlated with the ability of the inhibitors to removez inc ions from the labile zinc center of the enzyme. Ta ken together,the results of this pilot study suggest further evaluation of gold complexes as SARS-CoV antiviral drugs.
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.
A series of (NHC)Au(I)Cl monocarbene complexes and their gold(III) analogues (NHC)Au(III)Cl3 were prepared and investigated as antibacterial agents and inhibitors of bacterial TrxR. The complexes showed stronger antibacterial effects against the Gram‐positive MRSA and E. faecium strains than against several Gram‐negative bacteria. All complexes were efficient inhibitors of bacterial thioredoxin reductase, indicating that inhibition of this enzyme might be involved in their mechanism of action. The efficacy of gold(I) and gold(III) analogues was comparable in most of the assays. The cytotoxicity of the gold NHC compounds against cancer and human cells was overall weaker than the activity against the Gram‐positive bacteria, suggesting that their optimization as antibacterials warrants further investigation.
The Front Cover shows organometallic gold(III) complexes “attacking” pathogenic bacteria. Gold(I) and gold(III) complexes with N‐heterocylic carbene (NHC) ligands are efficient inhibitors of bacterial thioredoxin reductase (TrxR), making them antibiotic drug candidates with an unconventional mechanism of action. Their antibacterial effects are in particular very strong against some highly pathogenic Gram‐positive bacteria, such as methicillin resistant S. aureus. Cover design by Ella Maru Studio. More information can be found in the Full Paper by Ingo Ott et al.
The first title compound, [Au(C7H11BrN2)2]I, crystallizes in the space group P\overline{1} without imposed symmetry. The cations and anions are linked to form chains by Br...I...Br halogen-bond linkages. The second title compound, [Au(C7H11BrN2)2][AuI2(C7H11BrN2)2]I2, is an adduct of the first and its formally I2-oxidized AuIII analogue. It also crystallizes in space group P\overline{1}, whereby both gold atoms occupy inversion centres. The extended structure is a reticular layer involving Br...I...Br and I...I...Au linkages.
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