Insights on Structure–Passive Permeability Relationship in Pyrrole and Furan-Containing Macrocycles

Macrocycles have recognized therapeutic potential, but
their limited
cellular permeability can hinder their development as oral drugs.
To better understand the structure–permeability relationship
of heterocycle-containing, semipeptidic macrocycles, a library was
synthesized. These compounds were created by developing two novel
reactions described herein: the reduction of activated oximes by LiBH4 and the aqueous reductive mono-N-alkylation
of aldehydes using catalytic SmI2 and stoichiometric Zn.
The permeability of the macrocycles was evaluated through a parallel
artificial membrane permeability assay (PAMPA), and the results indicated
that macrocycles with a furan incorporated into the structure have
better passive permeability than those with a pyrrole moiety. Compounds
bearing a 2,5-disubstituted pyrrole (endo orientation)
were shown to be implicated in intramolecular H-bonds, enhancing their
permeability. This study highlighted the impact of heterocycles moieties
in semipeptides, creating highly permeable macrocycles, thus showing
promising avenues for passive diffusion of drugs beyond the rule-of-five
chemical space.