α-Ketoamides-based Covalent Inhibitors in Drug Discovery: Current Status and Synthetic Methods

The α-ketoamide moiety is abundant in natural products and has been incorporated by medicinal chemists into novel potential drug candidates. A variety of synthetic methods for preparing this privileged functional group have been disclosed. In this review, we will provide insights into the chemical reactivity of α-ketoamides, their successful incorporation into potent covalent inhibitors and an overview of the synthetic methodologies that are actively used in the discovery of small molecule α-ketoamide covalent inhibitors. Finally, this perspective aims to help medicinal chemists in overcoming synthetic challenges when introducing α-ketoamide groups into more efficient hit/lead molecules, and to highlight the popularity of α-ketoamide in drug design and development.