Property‐Driven Development of Passively Permeable Macrocyclic Scaffolds Using Heterocycles

Passive membrane permeability is a fundamental challenge in the development of bioactive macrocycles. To achieve this objective, chemists have resorted to various strategies, the most common of which is deployment of N‐methylated amino acids and/or D‐amino acids. Here we investigate the effect of heterocyclic grafts on the passive membrane permeability of macrocycles and report the structural consequences of iterative amino acid replacement by azole rings. Through stepwise substitution of amino acid residues for heterocycles, we show that lipophilicity and PAMPA permeability of a macrocycle can be vastly improved. Overall, changes in permeability do not scale linearly as more heterocycles are incorporated, underscoring the subtleties of conformation‐property relationships in this class of molecule. NMR analysis and molecular dynamics simulations provide insights into the structural consequences of the added heterocycles and these frameworks can now be applied as macrocyclic scaffolds for drug discovery. Peptide macrocycles display an array of bioactivity towards tough intracellular targets, but often exhibit poor physicochemical properties due to their multiple amide linkages. Here, the replacement of amide bonds with azole heterocycles is explored. The unique conformational space directed by heterocycles delivers macrocycles with high passive permeability, opening the door for the development of privileged macrocyclic scaffolds for drug discovery.