Prebiotic Synthesis of 3',5'-Cyclic Adenosine and Guanosine Monophosphates through Carbodiimide-Assisted Cyclization.

3',5'-Cyclic nucleotides play a fundamental role in modern biochemical processes and have been suggested to have played a central role at the origin of terrestrial life. In this work, we suggest that a formamide-based systems chemistry might account for their availability on the early Earth. In particular, we demonstrate that in a liquid formamide environment at elevated temperatures 3',5'-cyclic nucleotides are obtained in good yield and selectivity upon intramolecular cyclization of 5'-phosphorylated nucleosides in the presence of carbodiimides.

4-Alkyl-1,2,4-triazole-3-thione analogues as metallo-ß-lactamase inhibitors.

In Gram-negative bacteria, the major mechanism of resistance to ß-lactam antibiotics is the production of one or several ß-lactamases (BLs), including the highly worrying carbapenemases. Whereas inhibitors of these enzymes were recently marketed, they only target serine-carbapenemases (e.g. KPC-type), and no clinically useful inhibitor is available yet to neutralize the class of metallo-ß-lactamases (MBLs). We are developing compounds based on the 1,2,4-triazole-3-thione scaffold, which binds to the di-zinc catalytic site of MBLs in an original fashion, and we previously reported its promising potential to yield broad-spectrum inhibitors. However, up to now only moderate antibiotic potentiation could be observed in microbiological assays and further exploration was needed to improve outer membrane penetration. Here, we synthesized and characterized a series of compounds possessing a diversely functionalized alkyl chain at the 4-position of the heterocycle. We found that the presence of a carboxylic group at the extremity of an alkyl chain yielded potent inhibitors of VIM-type enzymes with Ki values in the µM to sub-µM range, and that this alkyl chain had to be longer or equal to a propyl chain. This result confirmed the importance of a carboxylic function on the 4-substituent of 1,2,4-triazole-3-thione heterocycle. As observed in previous series, active compounds also preferentially contained phenyl, 2-hydroxy-5-methoxyphenyl, naphth-2-yl or m-biphenyl at position 5. However, none efficiently inhibited NDM-1 or IMP-1. Microbiological study on VIM-2-producing E. coli strains and on VIM-1/VIM-4-producing multidrug-resistant K. pneumoniae clinical isolates gave promising results, suggesting that the 1,2,4-triazole-3-thione scaffold worth continuing exploration to further improve penetration. Finally, docking experiments were performed to study the binding mode of alkanoic analogues in the active site of VIM-2.

Formic Acid, a Ubiquitous but Overlooked Component of the Early Earth Atmosphere.

Terrestrial volcanism has been one of the dominant geological forces shaping our planet since its earliest existence. Its associated phenomena, like atmospheric lightning and hydrothermal activity, provide a rich energy reservoir for chemical syntheses. Based on our laboratory simulations, we propose that on the early Earth volcanic activity inevitably led to a remarkable production of formic acid through various independent reaction channels. Large-scale availability of atmospheric formic acid supports the idea of the high-temperature accumulation of formamide in this primordial environment.

Phosphoric acid salts of amino acids as a source of oligopeptides on the early Earth.

Because of their unique proton-conductivity, chains of phosphoric acid molecules are excellent proton-transfer catalysts. Here we demonstrate that this property could have been exploited for the prebiotic synthesis of the first oligopeptide sequences on our planet. Our results suggest that drying highly diluted solutions containing amino acids (like glycine, histidine and arginine) and phosphates in comparable concentrations at elevated temperatures (ca. 80 °C) in an acidic environment could lead to the accumulation of amino acid:phosphoric acid crystalline salts. Subsequent heating of these materials at 100 °C for 1-3 days results in the formation of oligoglycines consisting of up to 24 monomeric units, while arginine and histidine form shorter oligomers (up to trimers) only. Overall, our results suggest that combining the catalytic effect of phosphate chains with the crystalline order present in amino acid:phosphoric acid salts represents a viable solution that could be utilized to generate the first oligopeptide sequences in a mild acidic hydrothermal field scenario. Further, we propose that crystallization could help overcoming cyclic oligomer formation that is a generally known bottleneck of prebiotic polymerization processes preventing further chain growth.

Optimization of 1,2,4-Triazole-3-thiones toward Broad-Spectrum Metallo-ß-lactamase Inhibitors Showing Potent Synergistic Activity on VIM- and NDM-1-Producing Clinical Isolates.

Metallo-ß-lactamases (MBLs) contribute to the resistance of Gram-negative bacteria to carbapenems, last-resort antibiotics at hospital, and MBL inhibitors are urgently needed to preserve these important antibacterial drugs. Here, we describe a series of 1,2,4-triazole-3-thione-based inhibitors displaying an α-amino acid substituent, which amine was mono- or disubstituted by (hetero)aryl groups. Compounds disubstituted by certain nitrogen-containing heterocycles showed submicromolar activities against VIM-type enzymes and strong NDM-1 inhibition (Ki = 10-30 nM). Equilibrium dialysis, native mass spectrometry, isothermal calorimetry (ITC), and X-ray crystallography showed that the compounds inhibited both VIM-2 and NDM-1 at least partially by stripping the catalytic zinc ions. These inhibitors also displayed a very potent synergistic activity with meropenem (16- to 1000-fold minimum inhibitory concentration (MIC) reduction) against VIM-type- and NDM-1-producing ultraresistant clinical isolates, including Enterobacterales and Pseudomonas aeruginosa. Furthermore, selected compounds exhibited no or moderate toxicity toward HeLa cells, favorable absorption, distribution, metabolism, excretion (ADME) properties, and no or modest inhibition of several mammalian metalloenzymes.