Oxadiazoles in Medicinal Chemistry

Oxadiazoles are five-membered heteroaromatic rings containing
two
carbons, two nitrogens, and one oxygen atom, and they exist in different
regioisomeric forms. Oxadiazoles are frequently occurring motifs in
druglike molecules, and they are often used with the intention of
being bioisosteric replacements for ester and amide functionalities.
The current study presents a systematic comparison of 1,2,4- and 1,3,4-oxadiazole
matched pairs in the AstraZeneca compound collection. In virtually
all cases, the 1,3,4-oxadiazole isomer shows an order of magnitude
lower lipophilicity (log D), as compared to its isomeric
partner. Significant differences are also observed with respect to
metabolic stability, hERG inhibition, and aqueous solubil ity, favoring
the 1,3,4-oxadiazole isomers. The difference in profile between the
1,2,4 and 1,3,4 regioisomers can be rationalized by their intrinsically
different charge distributions (e.g., dipole moments). To facilitate
the use of these heteroaromatic rings, novel synthetic routes for
ready access of a broad spectrum of 1,3,4-oxadiazoles, under mild
conditions, are described.