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It has been hypothesised that drugs in the chemical space "beyond the rule of 5" (bRo5) must behave as molecular chameleons to combine otherwise conflicting properties, including aqueous solubility, cell permeability and target binding. Evidence for this has, however, been limited to the cyclic peptide cyclosporine A. Herein, we show that the non-peptidic and macrocyclic drugs roxithromycin, telithromycin and spiramycin behave as molecular chameleons, with rifampicin showing a less pronounced behaviour. In particular roxithromycin, telithromycin and spiramycin display a marked, yet limited flexibility and populate significantly less polar and more compact conformational ensembles in an apolar than in a polar environment. In addition to balancing of membrane permeability and aqueous solubility, this flexibility also allows binding to targets that vary in structure between species. The drugs' passive cell permeability correlates to their 3D polar surface area and corroborate two theoretical models for permeability, developed for cyclic peptides. We conclude that molecular chameleonicity should be incorporated in the design of orally administered drugs in the bRo5 space., (© 2020 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Dynamic chirality influences numerous processes in nature from protein folding to catalysis. Azapeptides are peptidomimetics possessing semicarbazide residues that can interconvert between sp 2 and sp 3 hybridization, resulting in stereodynamic interconversions of pseudo- R and - S -configurations by means of a planar intermediate. Cyclic azapeptides have shown unprecedented binding affinity to the cluster of differentiation 36 receptor (CD36) and ability to mitigate macrophage-driven inflammation by modulation of the toll-like receptor 2/6 pathway. A novel approach to synthesize cyclic peptides via A 3 -macrocyclization has been used to make R - and S -configuration controls to study the relevance of semicarbazide hybridization for modulator activity. Nuclear magnetic resonance spectroscopy analysis of potent cyclic azapeptide CD36 modulators (e.g., 1 and 2 ) and related cyclic peptides demonstrated that binding affinity correlated with conformational rigidity, and a hybridization preference for sp 2 > S - > R -sp 3 semicarbazide nitrogen configuration was evaluated. Evidence of the active conformation and the relevance for dynamic chirality serve as insights for creating cyclic (aza)peptide CD36 modulators to curb inflammation.