Bis(sulfonamide) isosters of mycophenolic adenine dinucleotide analogues : Inhibition of inosine monophosphate dehydrogenase

Abstract Synthesis of novel inhibitors of human IMP dehydrogenase is described. These inhibitors are isosteric methylenebis(sulfonamide) analogues 5 – 8 of earlier reported mycophenolic adenine methylenebis(phosphonate)s 1 – 3 . The parent bis(phosphonate) 1 and its bis(sulfonamide) analogue 5 showed similar sub-micromolar inhibitory activity against IMPDH2 ( K i  ∼ 0.2 μM). However, the bis(sulfonamide) analogues 6 and 8 substituted at the position 2 of adenine were approximately 3- to 10-fold less potent inhibitors of IMPDH2 ( K i  = 0.3–0.4 μM) than the corresponding parent bis(phosphonate)s 2 and 3 ( K i  = 0.04–0.11μM), respectively.