Discovery of 2,3-Diaminoindole Derivatives as a Novel Class of NOD Antagonists

NOD1
and NOD2 are members of the pattern recognition receptors
involved in the innate immune response. Overactivation of NOD1 is
implicated in inflammatory disorders, multiple sclerosis, and cancer
cell metastases. NOD1 antagonists would represent valuable pharmacological
tools to gain further insight into protein roles, potentially leading
to new therapeutic strategies. We herein report the expansion of the
chemical space of NOD1 antagonists via a multicomponent synthetic
approach affording a novel chemotype, namely, 2,3-diaminoindoles.
These efforts resulted in compound 37, endowed with low
micromolar affinity toward NOD1. Importantly, a proof-of-evidence
of direct binding to NOD1 of Noditinib-1 and derivative 37 is provided here for the first time. Additionally, the combination
of computational studies and NMR-based displacement assays enabled
the characterization of the binding modality of 37 to
NOD1, thus providing key unprecedented knowledge for the design of
potent and selective NOD1 antagonists.