Year: 2026
Type: preprint
Abstract: 2,3- and 2,4-Disubstituted 2-azabicyclo[3.n.1]alkanes (n = 1, 2) are introduced as bioisosteres of 1,2- and 1,3-disubstituted piperidines, respectively. The 2-azabicyclo[3.1.1]heptane and 2-azabicyclo[3.2.1]octane cores were constructed in a single step by a scalable intramolecular carbene N–H insertion, with subsequent functionalization giving α- and β-amino acids and other bifunctional derivatives amenable to two-point diversification. Structural analysis of the disubstituted 2-azabicyclo[3.1.1]heptane derivatives showed that both substitution patterns matched their reference piperidines in all exit vector parameters but one, and in that one occupied a geometry not observed for the parent ring. Virtual decoration of the functional groups on both 2-azabicyclo[3.n.1]alkane cores gave a library whose calculated physicochemical property profile coincided with that of the monocyclic reference, except for a modest increase in molecular weight. To validate the bioisosteric replacement in a biological context, conformationally restricted bupivacaine analogs based on both cores were prepared and evaluated in the mouse tail-flick assay. The 2-azabicyclo[3.1.1]heptane derivative reproduced the antinociceptive effect ofthe reference drug throughout the observation period, whereas the 2-azabicyclo[3.2.1]octane-derived counterpart retained only part ofthe reference activity.
Source: ChemRxiv
Language: English
Subfield: Organic Chemistry
Field: Chemistry
Domain: Physical Sciences
Open Access status: green
Funder: Enamine
OpenAlex ID: W7212292924