α-Methylene tetrazole-based peptidomimetics: synthesis and inhibition of HIV protease

Abstract

An α-methylene tetrazole-based dipeptidomimetic (11) has been prepared as a constrained and non-hydrolysable core for incorporation into peptides. A single crystal X-ray structure determination revealed that its solid-state conformation closely resembles that of the isosteric core of JG-365 bound to HIV protease. The α-methylene tetrazole isosteric unit was then incorporated into a number of peptide sequences and the resulting compounds 6–8 were assayed against HIV protease. The assay results suggest that the longer the C-terminal substitution the greater the potency, a result that reflects the interplay of the geometry of the tetrazole isostere and the C-terminal substituent.