Design, synthesis and biological evaluation of protease inhibitors containing morpholine cores with remarkable potency against both HIV-1 subtypes B and C.

ABSTRACT

By following up on the design vector of optimizing amine-based HIV-1 protease inhibitors, we have designed and biologically evaluated a novel class of inhibitors with the free nitrogen or sulphone in morpholine cores as P2 ligands in combination with diverse substituted phenylsulfonamide P2' ligands. As it turns out, a majority of these inhibitors exhibit prominent enzymatic inhibitory activity in low nanomolar ranges with relatively low cytotoxicity. Particularly, inhibitor 1e containing a morpholine carboxamide P2 ligand and a 4-hydroxyphenylsulfonamide P2' ligand illustrates a robust enzyme inhibitory IC50 value of 90 pM. Furthermore, 1e demonstrates impressive in vivo antiviral activity with EC50 value of 89 nM and a degree of inhibitory potency against the DRV-resistant variant. More importantly, 1e exhibits remarkable activity with EC50 values of 13.59 nM and 8.23 nM against subtype C HIV-1 strains ZM246 and Indie, respectively. Furthermore, the in silico studies provide molecular insights into binding features of inhibitors with HIV-1 protease, and furnish a valuable forecast on further process.