Antiviral Atropisomers: Conformational Energy Surfaces by NMR for Host-Directed Myxovirus Blockers

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• 作者：Craig Grimmer ; Terry W. Moore ; Aaron Padwa ; Andrew Prussia ; Gordon Wells ; Shaoxiong Wu ; Aiming Sun ; James P. Snyder
• 刊名：Journal of Chemical Information and Modeling
• 出版年：2014
• 出版时间：August 25, 2014
• 年：2014
• 卷：54
• 期：8
• 页码：2214-2223
• 全文大小：392K
• ISSN：1549-960X

文摘

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 螖Gp>p>猝?/sup>p> 鈮?0 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 p>3p>J_{C鈥揝鈥揅鈥揌} coupling constant was obtained by mapping the S鈥揅 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.