title: Antiviral atropisomers: conformational energy surfaces by NMR for host-directed myxovirus blockers.
abstract: Biologically active organic molecules characterized by a high single bond torsional barrier generate isolable isomers (atropisomers) and offer a unique stereochemical component to the design of selective therapeutic agents. The present work presents a nanomolar active inhibitor of myxoviruses, which most likely acts by blocking one or more cellular host proteins but also, serendipitously, exhibits axial chirality with an energy barrier of ΔG((++)) ≥30 kcal/mol. The latter has been probed by variable temperature NMR and microwave irradiation and by high level DFT transition state analysis and force field calculations. Full conformational profiles of the corresponding (aR,S) and (aS,S) atropisomers at ambient temperature were derived by conformer deconvolution with NAMFIS (NMR Analysis by Molecular Flexibility In Solution) methodology to generate seven and eight individual conformations, each assigned a % population. An accurate evaluation of a key torsion angle at the center of the molecules associated with a (3)JC-S-C-H coupling constant was obtained by mapping the S-C bond rotation with the MPW1PW91/6-31G-d,p DFT method followed by fitting the resulting dihedral angles and J-values to a Karplus expression. Accordingly, we have developed a complete conformational profile of diastereomeric atropisomers consistent with both high and low rotational barriers. We expect this assessment to assist the rationalization of the selectivity of the two (aR,S) and (aS,S) forms against host proteins, while offering insights into their divergent toxicity behavior.
authors: School of Chemistry and Physics, University of KwaZulu-Natal , Pietermaritzburg, South Africa.
authors: Craig
authors: C
authors: Grimmer
authors: Terry W
authors: TW
authors: Moore
authors: Aaron
authors: A
authors: Padwa
authors: Andrew
authors: A
authors: Prussia
authors: Gordon
authors: G
authors: Wells
authors: Shaoxiong
authors: S
authors: Wu
authors: Aiming
authors: A
authors: Sun
authors: James P
authors: JP
authors: Snyder
mesh_terms: D000818:Animals; D000998:Antiviral Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D001562:Benzimidazoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D018360:Crystallography, X-Ray; D005057:Eukaryotic Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology / Q000821:virology; D058605:Host-Derived Cellular Factors / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D008024:Ligands; D009682:Magnetic Resonance Spectroscopy; D008968:Molecular Conformation; D009975:Orthomyxoviridae / Q000187:drug effects* / Q000502:physiology; D011485:Protein Binding; D011789:Quantum Theory; D054852:Small Molecule Libraries / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D013237:Stereoisomerism; D013816:Thermodynamics
chemical_list: D000998:Antiviral Agents; D001562:Benzimidazoles; D058605:Host-Derived Cellular Factors; D008024:Ligands; D054852:Small Molecule Libraries