Design of inhibitors of scytalone dehydratase: probing interactions with an asparagine carboxamide.

Among the active-site residues of scytalone dehydratase, the side-chain carboxamide of asparagine 131 has the greatest potential for strong electrostatic interactions. Structure-based inhibitor design aimed at enhancing interactions with this residue led to the synthesis of a series of highly potent inhibitors that have a five- or six-membered ring containing a carbonyl functionality for hydrogen bonding. To achieve a good orientation for hydrogen bonding, the inhibitors incorporate a phenyl substituent that displaces a phenylalanine residue away from the five- or six-membered rings.