In this review we provide a brief historic overview of covalent inhibitors and summarize recent advances focusing on developments in the last decade. Applications in challenging targets and future perspectives are also discussed.
The area of covalent inhibitors is gaining momentum due to recently introduced clinical drugs, but libraries of these compounds are scarce. Multicomponent reaction (MCR) chemistry is well known for its easy access to a very large and diverse chemical space. Here, we show that MCRs are highly suitable to generate libraries of electrophiles based on different scaffolds and three-dimensional shapes and highly compatible with multiple functional groups. According to the building block principle of MCR, acrylamide, acrylic acid ester, sulfurylfluoride, chloroacetic acid amide, nitrile, and α,β-unsaturated sulfonamide warheads can be easily incorporated into many different scaffolds. We show examples of each electrophile on 10 different scaffolds on a preparative scale as well as in a high-throughput synthesis mode on a nanoscale to produce libraries of potential covalent binders in a resource- and time-saving manner. Our operational procedure is simple, mild, and step economical to facilitate future covalent library synthesis.
A series
of unprecedented tetrazole-linked imidazo[1,5-a]pyridines
are synthesized from simple and readily available
building blocks. The reaction sequence involves an azido-Ugi-deprotection
reaction followed by an acetic anhydride-mediated N-acylation–cyclization process to afford the target heterocycle.
Furthermore, the scope of the methodology was extended to diverse
R3-substitutions by employing commercial anhydrides, acid
chlorides, and acids as an acyl component. The scope for the postmodification
reactions are explored and the usefulness of the synthesis is exemplified
by an improved three-step synthesis of a guanylate cyclase stimulator.
Protein crystallography (PX) is widely used to drive advanced stages of drug optimization or to discover medicinal chemistry starting points by fragment soaking. However,recent progress in PX could allowfor amore integrated role into early drug discovery.H ere,w ed emonstrate for the first time the interplay of high throughput synthesis and high throughput PX. We describe ap ractical multicomponent reaction approach to acrylamides and -esters from diverse building blocks suitable for mmol scale synthesis on 96-well format and on ah igh-throughput nanoscale format in ah ighly automated fashion. High-throughput PX of our libraries efficiently yielded potent covalent inhibitors of the main protease of the COVID-19 causing agent, SARS-CoV-2. Our results demonstrate,t hat the marriage of in situ HT synthesis of (covalent) libraires and HT PX has the potential to accelerate hit finding and to provide meaningful strategies for medicinal chemistry projects.
A 21 membered library of 2‐(imidazo[1,5‐α]pyridine‐1‐yl)‐1,3,4‐oxadiazoles is synthesized in an unprecedented short sequence starting from an Ugi tetrazole reaction with a cleavable isocyanide component. The intermediate tetrazole is subjected to an acetic anhydride‐mediated cyclization, followed by a Huisgen‐type rearrangement with acyl chlorides to afford the imidazopyridine‐oxadiazole bis‐heterocycles. The scope and limitations of the methodology were investigated with substitutions on both the oxadiazole and the imidazopyridine rings. The introduced enabling technology for imidazopyridine oxadiazole synthesis combines a short reaction sequence with high scaffold diversity, based on commercially available starting materials and high functional groups tolerance.
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