Reviews & Reactions: C-H Borylation of BCPs, Magic Chloro, and More

This “journal club” article highlights five recent articles of general interest to drug discovery scientists, including reviews on therapeutic areas of interest, principles and areas of medicinal chemistry and pharmacology, and a synthetic transformation worth keeping in mind.

1. A “Magic Chloro” Med. Chem. Review

D. Chiodi and Y. Ishihara (Vividion)
J. Med. Chem., Apr. 4, 2023
https://pubs.acs.org/doi/10.1021/acs.jmedchem.2c02015

Like “magic methyl” groups, certain chlorine substitutions can lead to outsized impacts on drug properties for a variety of reasons. These “magic chloro” groups have been observed to increase potency thousands-fold, punching well above their weight lipophilicity-wise. This tour-de-force review from Yoshihiro Ishihara of Vividion Therapeutics and Debora Chiodi at Scripps compiles examples of chlorine atoms exerting outsized effects on SAR. One notable example comes from an HIV reverse transcriptase program led by Andy Peat, then at GSK, in 2012. A hydrogen-to-chlorine substitution in this case led to a >1300x boost in potency, driven by a combination of Van der Waals interactions, conformational effects, and influence on imidazole acidity.