title: Stereoelectronic effects dictate molecular conformation and biological function of heterocyclic amides.
abstract: Heterocycles adjacent to amides can have important influences on molecular conformation due to stereoelectronic effects exerted by the heteroatom. This was shown for imidazole- and thiazole-amides by comparing low energy conformations (ab initio MP2 and DFT calculations), charge distribution, dipole moments, and known crystal structures which support a general principle. Switching a heteroatom from nitrogen to sulfur altered the amide conformation, producing different three-dimensional electrostatic surfaces. Differences were attributed to different dipole and orbital alignments and spectacularly translated into opposing agonist vs antagonist functions in modulating a G-protein coupled receptor for inflammatory protein complement C3a on human macrophages. Influences of the heteroatom were confirmed by locking the amide conformation using fused bicyclic rings. These findings show that stereoelectronic effects of heterocycles modulate molecular conformation and can impart strikingly different biological properties.
authors.affiliation: Division of Chemistry and Structural Biology, Institute for Molecular Bioscience, The University of Queensland , Brisbane, QLD 4072, Australia.
authors.forename: Robert C
authors.initials: RC
authors.lastname: Reid
authors.forename: Mei-Kwan
authors.initials: MK
authors.lastname: Yau
authors.forename: Ranee
authors.initials: R
authors.lastname: Singh
authors.forename: Junxian
authors.initials: J
authors.lastname: Lim
authors.forename: David P
authors.initials: DP
authors.lastname: Fairlie
mesh_terms: D000577:Amides / Q000737:chemistry* / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism; D002478:Cells, Cultured; D004563:Electrochemistry; D006571:Heterocyclic Compounds / Q000737:chemistry* / Q000494:pharmacology; D006801:Humans; D007093:Imidazoles / Q000737:chemistry / Q000494:pharmacology; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism; D008958:Models, Molecular; D008968:Molecular Conformation; D013237:Stereoisomerism; D013844:Thiazoles / Q000737:chemistry / Q000494:pharmacology
chemical_list: D000577:Amides; D006571:Heterocyclic Compounds; D007093:Imidazoles; D013844:Thiazoles; D002118:Calcium