Allophenylnorstatine-containing HIV-1 protease inhibitors: design, synthesis and structure-activity relationships for selected P

ABSTRACT

The design and development of potent HIV protease inhibitors remain an attractive target for antiviral therapy. A novel class of HIV protease inhibitors containing allophenylnorstatine [Apns; [2S,3S]-3-amino-2-hydroxy-4-phenylbutyric acid] as a transition state mimic have been reported. In this work we fixed P 2' [as tert-butylamino or 2-methylbenzylamino] and changed P 2 moiety to provide two series of dipeptide analogs. Preliminary evaluation of the activity of the synthesized derivatives were determined as percentage of enzyme inhibition at 5 microM level. The results showed that the introduction of 2-methylbenzylamino moiety as P 2' ligand 6a-e considerably improved HIV inhibitory activity in comparison with the tert-butyl amino analogs 5a-e. It was found that compounds in both series retained activity still less than the lead compounds KNI-577 and KNI-727