Isonitrile-Based Multicomponent Synthesis of β-Amino Boronic Acids as β-Lactamase Inhibitors.

Emanuele Bassini,Giovanni Grazioso,Jean-Denis Docquier,Filomena Sannio,Jacopo Sgrignani,Alessandra Silvani,Stefano Gazzotti,Leonardo Lo Presti

doi:10.3390/antibiotics9050249

Emanuele Bassini, Giovanni Grazioso + Show 6 more

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https://doi.org/10.3390/antibiotics9050249

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Abstract

The application of various isonitrile-based multicomponent reactions to protected (2-oxoethyl)boronic acid (as the carbonyl component) is described. The Ugi reaction, both in the four components and in the four centers–three components versions, and the van Leusen reaction, proved effective at providing small libraries of MIDA-protected β-aminoboronic acids. The corresponding free β-aminoboronic acids, quantitatively recovered through basic mild deprotection, were found to be quite stable and were fully characterized, including by 11B-NMR spectroscopy. Single-crystal X-ray diffraction analysis, applied both to a MIDA-protected and a free β-aminoboronic acid derivative, provided evidence for different conformations in the solid-state. Finally, the antimicrobial activities of selected compounds were evaluated by measuring their minimal inhibitory concentration (MIC) values, and the binding mode of the most promising derivative on OXA-23 class D β-lactamase was predicted by a molecular modeling study.

Highlights

The recent interest in using boron in medicinal chemistry is due to the reliable fact that boron is a versatile atom, potentially not toxic, and able to play an important role in drug design [1].The presence of an empty p-orbital promotes the conversion of the boron center from neutral trigonal planar sp2 to tetrahedral sp3 hybridization, imparting peculiar chemical behaviors to boron-containing compounds
Some of them have been developed as drugs and recently received FDA approval, such as bortezomib, for the treatment of multiple myeloma, Antibiotics 2020, 9, 249; doi:10.3390/antibiotics9050249
Even though multicomponent reactions (MCRs) run best in methanol and trifluoroethanol, we looked at aprotic solvents, such as acetonitrile, dioxane, and toluene, in order to preserve the MIDA-protecting group

Summary

Introduction

The recent interest in using boron in medicinal chemistry is due to the reliable fact that boron is a versatile atom, potentially not toxic, and able to play an important role in drug design [1]. The presence of an empty p-orbital promotes the conversion of the boron center from neutral trigonal planar sp to tetrahedral sp hybridization, imparting peculiar chemical behaviors to boron-containing compounds. Thanks to the empty p-orbital, boronic acids can form tetracoordinate “ate” complexes by interacting with nucleophilic groups, including the side chains of some amino acids such as hydroxyl of serine and threonine. Some of them have been developed as drugs and recently received FDA approval, such as bortezomib, for the treatment of multiple myeloma, Antibiotics 2020, 9, 249; doi:10.3390/antibiotics9050249 www.mdpi.com/journal/antibiotics myeloma, and vaborbactam, a potent inhibitor of β-lactamase (BL) enzymes, approved for use in combination with meropenem

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