Synthesis of potent inhibitors of histidinol dehydrogenase

Novel inhibitors of histidinol dehydrogenase are described. The most potent inhibitors, compounds 18 (K-i* = 4.4 nM) and 19 (K-i* = 2.9 nM) exploit a hitherto unreported lipophilic binding pocket adjoining the active site. Preliminary SAR data for this pocket are detailed. The electrophilic ketone 6 designed to bind to an active site nucleophile was a considerably weaker inhibitor (IC50 similar to 20 mu M). Copyright (C) 1996 Elsevier Science Ltd