This article contributes a highly
accurate model for predicting
the melting points (MPs) of medicinal chemistry compounds. The model
was developed using the largest published data set, comprising more
than 47k compounds. The distributions of MPs in drug-like and drug
lead sets showed that >90% of molecules melt within [50,250]°C.
The final model calculated an RMSE of less than 33 °C for molecules
from this temperature interval, which is the most important for medicinal
chemistry users. This performance was achieved using a consensus model
that performed calculations to a significantly higher accuracy than
the individual models. We found that compounds with reactive and unstable
groups were overrepresented among outlying compounds. These compounds
could decompose during storage or measurement, thus introducing experimental
errors. While filtering the data by removing outliers generally increased
the accuracy of individual models, it did not significantly affect
the results of the consensus models. Three analyzed distance to models
did not allow us to flag molecules, which had MP values fell outside
the applicability domain of the model. We believe that this negative
result and the public availability of data from this article will
encourage future studies to develop better approaches to define the
applicability domain of models. The final model, MP data, and identified
reactive groups are available online at .
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.
Straightforward practical synthetic approaches to 3,4-bis- and 3,4,5-tris(trifluoromethyl)pyrazoles have been developed. The key step of the both syntheses is a transformation of the carboxylic group in a pyrazole core into the trifluoromethyl group by sulfur tetrafluoride. The elaborated synthetic protocols allow gram-scale preparation of the target products. The obtained compounds are comprehensively characterized by means of crystallographic analysis, determination of pK(a) values and fluorescence measurements.
We report a fast-track computationally-driven discovery of new SARS-CoV2 Main Protease M$pro inhibitors whose potency range from mM for initial non-covalent ligands to sub-μM for the final covalent compound (IC50=830...
A series of GABA analogs and related mono‐ and bifunctional building blocks based on the monofluorinated 1,3‐disubstituted cyclobutane scaffold was designed and synthesized. The synthetic approaches included desilylative deoxyfluorination of TMS‐protected cyanohydrin and iodofluorination of methylenecyclobutane carboxylate as the key steps. Both approaches were highly efficient for the multigram synthesis of γ‐ and δ‐amino acids, monoprotected diamines, amino alcohols, and hydroxy acids. The first method was diastereoselective (dr 3:1) but it failed to produce the target products as pure, separable diastereomers. On the contrary, the second approach lacked diastereoselectivity but provided pure cis and trans isomers of the corresponding fluorocyclobutanes by separation of diastereomers; the products were obtained on up to 100 g scale in a single run. Moreover, the method was applied for the preparation of 3‐azabicyclo[3.1.1]heptane derivatives. X‐ray diffraction studies showed that the synthesized building blocks are appropriate analogs of GABA with either somewhat larger or smaller size as compared to the parent amino acid.
Addition reactions of perfluoroalkyl radicals to ordinary or polyfluorinated alkenes have been frequently used to synthesize perfluoroalkylated organic compounds. Here ethyl/methyl 2-bromo-2,2-difluoroacetate, diethyl (bromodifluoromethyl)phosphonate, [(bromodifluoromethyl)sulfonyl]benzene, and ethyl 2-bromo-2-fluoroacetate were involved in Na2S2O4-mediated radical additions to vinyl ethers in the presence of alcohols to give difluoro or monofluoroacetyl-substituted acetals or corresponding difluoromethylphosphonate- and (difluoromethylphenyl)sulfonyl-substituted alkyl acetals. This methodology has also been applied as a key step in the synthesis of hitherto unknown 3,3-difluoro-GABA, completing the series of isomeric difluoro GABAs. Comparison of the pKa values of 3-fluoro- and 3,3-difluoro-GABA with that of the fluorine free parent compound showed that introduction of each fluorine lead to acidification of both the amino and the carboxyl functions by approximately one unit.
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