Synthesis of 1,2,5-thiadiazolidin-3-one 1,1-dioxide derivatives and evaluation of their affinity for MHC class-II proteins

1,2,5-Thiadiazolidin-3-one 1,1-dioxide derivatives (+/-)-1a-d and (+/-)-2 w ere designed by molecular modeling as MHC (major histocompatibility complex ) class-II inhibitors. They were prepared from the unsymmetrically N,N'-dis ubstituted acyclic sulfamides (+/-)-4a-d (Scheme 1) and (+/-)-11 (Scheme 2) . These N-alkyl-N'-arylsulfamide precursors were: synthesized by nucleophil ic substitution of either a sulfamoyl-chloride or a N-sulfamoyloxazolidinon e. Extension of base-induced cyclization methods from aliphatic to aromatic sulfamides gave access to the desired target molecules. The N-alkyl-1,2,5- thiadinzolidin-3-one 1,1-dioxide derivatives (+/-)-3a-c mere also prepared by the oxazolidinone route (Scheme 4) for coupling to a tetrapeptide fragme nt. The X-ray crystal structure of 1,2,5-thiadiazolidin-3-one 1,1-dioxide ( +/-)-21a was solved, and the directionality of the H-bond donor (N-H) and a cceptor (SO2) groups of the cyclic scaffold determined (Figs. 1 and 2). The pit, value of the N-H group in (+/-)-21a was determined by H-1-NMR titrati on as 11.9 (Fig. 3). Compounds (+/-)-1a-d were shown to inhibit competition peptide binding to HLA-DR4 molecules in the single-digit millimolar concen tration range.