Diaryl-Substituted (Dihydro)pyrrolo[3,2,1-hi]indoles, a Class of Potent COX‑2 Inhibitors with Tricyclic Core Structure

A new compound class of diaryl-substituted heterocycles with tricyclic dihydropyrrolo­[3,2,1-hi]­indole and pyrrolo­[3,2,1-hi]­indole core structures has been designed and was synthesized by a modular sequence of Friedel–Crafts acylation, amide formation, and McMurry cyclization. This synthesis route represents a novel and versatile access toward dihydropyrrolo­[3,2,1-hi]­indoles and is characterized by good chemical yields and high modularity. From a set of 19 derivatives, 11 candidates were selected for determination of their COX inhibition potency and were found to be selective inhibitors with high affinity to COX-2 (IC50 ranging from 20–2500 nM and negligible inhibition of COX-1). The binding mode of the novel inhibitors in the active side of COX-2 was calculated in silico using the protein–ligand docking program GOLD by application of the molecular structures of two compounds derived from X-ray crystallography. Two novel compounds with high affinity to COX-2 (6k = 70 nM, 8e = 60 nM) have a fluoro substituent, making them promising candidates for the development of 18F-radiolabeled COX-2 inhibitors for imaging purposes with positron emission tomography (PET).