From garden to lab: C-3 chemical modifications of tomatidine unveil broad-spectrum ATP synthase inhibitors to combat bacterial resistance.

Antibiotic resistance is escalating alarmingly worldwide. Bacterial resistance mechanisms are surfacing and proliferating across the globe, jeopardizing our capacity to manage prevalent infectious illnesses. Without drastic measures, we risk entering a post-antibiotic era, where even trivial infections and injuries can cause death again. In this context, we have developed a new class of antibiotics based on tomatidine (TO), a natural product derived from tomato plants, with a novel mode of action by targeting bacterial ATP synthases. The first generation of compounds proved highly specific for small-colony variants (SCVs) of Staphylococcus aureus. However, optimization of this scaffold through extensive structure-activity relationship studies has enabled us to broaden its effectiveness to include both Gram-positive and Gram-negative bacteria. Notably, the results showed that specific C3-modification of TO could improve ATP synthase inhibition and also bypass the outer membrane barrier of Gram-negative bacteria to gain substantial growth inhibition including against multi-resistant strains.

Electrophile promoted cyclization of ortho-aryl substituted ynamides: construction of 3-amino-4-halo- or 4 seleno-isocoumarin derivatives.

Isocoumarins are important building blocks in medicinal chemistry. They are widespread in the core structure of biologically active compounds. Here we report the development of an efficient and highly reactive electrophilic cyclization of ortho-ynamidyl benzoate esters providing access to 3-amino-4-halo- or 4-seleno-isocoumarins in a short time (<1 min) with good yields.

Copper-catalyzed transformation of alkyl nitriles to N-arylacetamide using diaryliodonium salts.

This work reports a simple and efficient method for the copper-catalyzed redox-neutral transformation of alkyl nitriles using eco-friendly diaryliodonium salts and leading to N-arylacetamides. The method features high efficiency, broad substrate scope and good functional group tolerance.

Rapid synthesis of 3-amino-1H-isochromene from ortho-ynamidyl het(aryl) aldehyde derivatives.

A simple and original efficient synthesis of 3-amino-1H-isochromene bearing a bromine atom at the C-1 position via a 6-endo-cyclization approach from in situ generated ortho-ynamidyl het(aryl) aldehyde derivatives is achieved under mild reaction conditions and with good yields. Original ortho-ynamidyl benzaldehyde compounds were also successfully obtained.

Access to Unprotected ß-Fluoroalkyl ß-Amino Acids and Their α-Hydroxy Derivatives.

Unprotected ß-(het)aryl-ß-fluoroalkyl ß-amino acids and their α-hydroxy derivatives can be readily obtained using a decarboxylative Mannich-type reaction without protection/deprotection steps. This protocol utilizes lithium hexamethyldisilazide and (het)arylfluoroalkyl ketones to generate NH-ketimine intermediates. The mild reaction conditions allow the preparation of original fluorinated ß-amino acids as useful building blocks in a practical and scalable manner.