Development of Novel Membrane Disrupting Lipoguanidine Compounds Sensitizing Gram-Negative Bacteria to Antibiotics.

A new class of amphiphilic molecules, the lipoguanidines, designed as hybrids of guanidine and fatty acid compounds, has been synthesized and developed. The new molecules present both a guanidine polar head and a lipophilic tail that allow them to disrupt bacterial membranes and to sensitize Gram-negative bacteria to the action of the narrow-spectrum antibiotics rifampicin and novobiocin. The lipoguanidine 5g sensitizes Klebsiella pneumonia, Acinetobacter baumannii, Pseudomonas aeruginosa, and Escherichia coli to rifampicin, thereby reducing the antibiotic minimum inhibitory concentrations (MIC) up to 256-fold. Similarly, 5g is able to potentiate novobiocin up to 64-fold, thereby showing a broad spectrum of antibiotic potentiating activity. Toxicity and mechanism studies revealed the potential of 5g to work synergistically with rifampicin through the disruption of bacterial membranes without affecting eukaryotic cells.

Oxazolidinones as versatile scaffolds in medicinal chemistry.

Oxazolidinone is a five-member heterocyclic ring with several biological applications in medicinal chemistry. Among the three possible isomers, 2-oxazolidinone is the most investigated in drug discovery. Linezolid was pioneered as the first approved drug containing an oxazolidinone ring as the pharmacophore group. Numerous analogues have been developed since its arrival on the market in 2000. Some have succeeded in reaching the advanced stages of clinical studies. However, most oxazolidinone derivatives reported in recent decades have not reached the initial stages of drug development, despite their promising pharmacological applications in a variety of therapeutic areas, including antibacterial, antituberculosis, anticancer, anti-inflammatory, neurologic, and metabolic diseases, among other areas. Therefore, this review article aims to compile the efforts of medicinal chemists who have explored this scaffold over the past decades and highlight the potential of the class for medicinal chemistry.

Antimicrobial drugs bearing guanidine moieties: A review.

Compounds incorporating guanidine moieties constitute a versatile class of biologically interesting molecules with a wide array of applications. As such, guanidines have been exploited as privileged structural motifs in designing novel drugs for the treatment of various infectious and non-infectious diseases. In designing anti-infective agents, this moiety carries great appeal by virtue of attributes such as hydrogen-bonding capability and protonatability at physiological pH in the context of interaction with biological targets. This review provides an overview of recent advances in hit-to-lead development studies of antimicrobial guanidine-containing compounds with the aim to highlight their structural diversity and the pharmacological relevance of the moiety to drug activity, insofar as possible. In so doing, emphasis is put on chemical and microbiological properties of such compounds in relation to antibacterial, antifungal and antimalarial activities.

Development of photoactivable phenanthroline-based manganese(I) CO-Releasing molecules (PhotoCORMs) active against ESKAPE bacteria and bacterial biofilms.

The synthesis and biological evaluation of a series of phenanthroline-based visible-light-activated manganese(I) carbon-monoxide-releasing molecules (PhotoCORMs) against ESKAPE bacteria and bacterial biofilms is reported. Four carbonyl compounds of general formula fac-[Mn(N∧N)(CO)3(L)] have been synthesized and characterized. Despite being thermally stable in the absence of light, these PhotoCORMs readily release CO upon blue (435-450 nm) LED light irradiation as confirmed by spectrophotometric CO releasing experiments (Mb Assay). The antibacterial activity of the four PhotoCORMs has been investigated against a panel of ESKAPE bacteria. The compounds 1-3 were found to be effective antibacterials at low concentrations against multidrug-resistant Klebsiella pneumoniae and Acinetobacter baumannii when photoactivated with blue-light. In addition, the PhotoCORMs 1-2 were found to inhibit the formation of Klebsiella pneumoniae and Acinetobacter baumannii bacterial biofilms at low concentrations (MIC = 4-8 µg/mL), turning out to be promising candidates to combat antimicrobial resistance. The antibacterial and biofilm inhibitory effect of the PhotoCORMs is plausibly due to the release of CO as well as the formation of phenanthroline photo-by-products as revealed by spectroscopy and microbiology experiments.

A mild and chemoselective CALB biocatalysed synthesis of sulfoxides exploiting the dual role of AcOEt as solvent and reagent.

A mild, chemoselective and sustainable biocatalysed synthesis of sulfoxides has been developed exploiting CALB and using AcOEt with a dual role of more environmentally friendly reaction solvent and enzyme substrate. A series of sulfoxides, including the drug omeprazole, have been synthesised in high yields and with excellent E-factors.