Pyrazolo-isothiazole dioxide: an interesting scaffold for the preparation of peptidomimetics

There are many examples in literature of peptidomimetics that incorporate a heterocycle scaffold into a peptide, or a peptide-like sequence. The pre-organization of peptide shape, via the introduction of a structural heterocyclic motif that imparts conformational restriction, can enhance binding and hence therapeutic potential.1 Hitherto the standard approach to combine heterocycles and peptides has been to functionalize the side chain or the N/C termini of an amino acid building block with the heterocyclic moiety.2 A few examples have been accomplished in which the heterocycles are part of the peptide backbone itself.3 By the way of a 1,3-dipolar cycloaddition reaction between diazoacetates 2 and the high reactive double bond of the 3-amino isothiazole dioxide partner 1, the adducts 3 are obtained in high yield and complete regioselectivity. The presence in compounds 3 of the carboxylic substituent and the pyrazole NH group can be exploited for coupling reaction with amino acids. By this way a peptide sequence can be generated characterized by the rigid planar geometry of the heterocyclic system favoring a particular orientation of the growing peptide chain (Figure). Moreover the presence of the sulfonyl group as well as the NH group at C-3 is of interest. They can behave as hydrogen bond acceptor and donor, respectively, giving raise to interactions with proteins or other potential targets. The synthesis of model peptidomimetics containing the heterocyclic scaffold, NMR analyses and computational studies are reported.