Rhenium(I) derivatives of aminoquinoline and imidazolopiperidine-based ligands: Synthesis, in vitro and in silico biological evaluation against Plasmodium falciparum.

A small library of aminoquinoline and imidazolopiperidine (IMP)-based ligands, containing the 1,2,3-triazole moiety, and their corresponding tricarbonyl rhenium complexes were synthesised and their inhibitory activities evaluated against the chloroquine-sensitive (CQS) and multidrug-resistant (MDR) strains (NF54 and K1, respectively) of P. falciparum. The quinoline-based compounds (L1, L2, ReL1, and ReL2) were at least six-fold more potent than their IMP-based counterparts (L3, L4, ReL3, and ReL4) against both strains of P. falciparum, with the most promising compound (L1) displaying activity comparable to chloroquine diphosphate (CQDP) in the MDR strain. Additionally, all of the synthesised compounds have resistance indices less than CQDP. To gain insight into a possible mechanism of action, in silico hemozoin docking simulations were performed. These studies proposed that the tested compounds may act via hemozoin inhibition, as the new aminoquinoline-derivatives, with the exception of complex ReL2 (binding affinity: -12.62 kcal/mol), showed higher binding affinities than the reference drug chloroquine (CQ, -13.56 kcal/mol). Furthermore, the ligands exhibited superior binding affinity relative to their corresponding Re(I) complexes, which is reflected in their antiplasmodial activity.

Combatting AMR: A molecular approach to the discovery of potent and non-toxic rhenium complexes active against C. albicans-MRSA co-infection.

Antimicrobial resistance (AMR) is a major emerging threat to public health, causing serious issues in the successful prevention and treatment of persistent diseases. While the problem escalates, lack of financial incentive has lead major pharmaceutical companies to interrupt their antibiotic drug discovery programs. The World Health Organisation (WHO) has called for novel solutions outside the traditional development pathway, with emphasis on new classes of active compounds with non-classical mechanisms of action. Metal complexes are an untapped source of antibiotic potential owing to unique modes of action and a wider range of three-dimensional geometries as compared to purely organic compounds. In this study, we present the antimicrobial and antifungal efficacy of a family of rhenium tricarbonyl diimine complexes with varying ligands, charge and lipophilicity. Our study allowed the identification of potent and non-toxic complexes active in vivo against S. aureus infections at MIC doses as low as 300 ng/mL, as well as against C. albicans-MRSA mixed co-infection. The compounds are capable of suppressing the C. albicans morphogenetic yeast-to-hyphal transition, eradicating fungal-S. aureus co-infection, while showing no sign of cardio-, hepato-, hematotoxiciy or teratogenicity.

Design, synthesis and in vivo evaluation of 3-arylcoumarin derivatives of rhenium(I) tricarbonyl complexes as potent antibacterial agents against methicillin-resistant Staphylococcus aureus (MRSA).

We have prepared a series of ten 3-arylcoumarin molecules, their respective fac-[Re(CO)3(bpy)L]+ and fac-[Re(CO)3(L⁀L)Br] complexes and tested all compounds for their antimicrobial efficacy. Whereas the 3-arylcoumarin ligands are virtually inactive against the human-associated pathogens with minimum inhibitory concentrations (MICs) > 150 µM, when coordinated to the fac-[Re(CO)3]+ core, most of the resulting complexes showed remarkable antibacterial potency. Several rhenium complexes exhibit activity in nanomolar concentrations against Gram-positive pathogens such as Staphylococcus aureus strains, including methicillin-resistant S. aureus (MRSA) and Enterococcus faecium. The molecules do not affect bacterial cell membrane potential, but some of the most potent complexes strongly interact with DNA, indicating it as a possible target for their mode of action. In vivo studies in the zebrafish model showed that the complexes with anti-staphylococcal/MRSA activity were non-toxic to the organism even at much higher doses of the corresponding MICs. In the zebrafish-MRSA infection model, the complexes increased the survival rate of infected fish up to 100% and markedly reduced bacterial burden. Moreover, all rescued fish developed normally following the treatments with the metallic compounds.