Physico‐chemical properties important to drug discovery (pKa, LogP, and aqueous solubility), as well as metabolic stability, were studied for a series of functionalized gem‐difluorinated cycloalkanes and compared to those of non‐fluorinated and acyclic counterparts to evaluate the impact of the fluorination. It was found that the influence of the CF2 moiety on the acidity/basicity of the corresponding carboxylic acids and amines was defined by inductive the effect of the fluorine atoms and was nearly the same for acyclic and cyclic aliphatic compounds. Lipophilicity and aqueous solubility followed more complex trends and were affected by the position of the fluorine atoms, ring size, and even the nature of the functional group present; also, significant differences were found for the acyclic and cyclic series. Also, gem‐difluorination either did not affect or slightly improved the metabolic stability of the corresponding model derivatives. The presented results can be used as a guide for rational drug design employing fluorine and establish the first chapter in a catalog of the key in vitro properties of fluorinated cycloalkanes.
Herein we provide a living summary of the data generated during the COVID Moonshot project focused on the development of SARS-CoV-2 main protease (Mpro) inhibitors. Our approach uniquely combines crowdsourced medicinal chemistry insights with high throughput crystallography, exascale computational chemistry infrastructure for simulations, and machine learning in triaging designs and predicting synthetic routes. This manuscript describes our methodologies leading to both covalent and non-covalent inhibitors displaying protease IC50 values under 150 nM and viral inhibition under 5 uM in multiple different viral replication assays. Furthermore, we provide over 200 crystal structures of fragment-like and lead-like molecules in complex with the main protease. Over 1000 synthesized and ordered compounds are also reported with the corresponding activity in Mpro enzymatic assays using two different experimental setups. The data referenced in this document will be continually updated to reflect the current experimental progress of the COVID Moonshot project, and serves as a citable reference for ensuing publications. All of the generated data is open to other researchers who may find it of use.
An
efficient approach to synthesis of previously unavailable 2-substituted
difluorocyclobutane building blocks was developed and applied on a
multigram scale. The key step of the synthetic sequence included deoxofluorination
of O-protected 2-(hydroxylmethyl)cyclobutanone. Dissociation
constants (pK
a) and log P values for 2,2-difluorocyclobutaneamine and 2,2-difluorocyclobutanecarboxylic
acid or their derivatives were measured and compared with the values
obtained for the corresponding 3,3-difluorocyclobutane derivatives
and nonfluorinated counterparts. Three-dimensional structures of 2,2-
and 3,3-difluorocyclobutanamines were compared using exit vector plot
analysis of X-ray crystallographic data.
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