Evaluation of darunavir-derived HIV-1 protease inhibitors incorporating P2' amide-derivatives: Synthesis, biological evaluation and structural studies

Abstract

We report here the synthesis and biological evaluation of darunavir derived HIV-1 protease inhibitors and their functional effect on enzyme inhibition and antiviral activity in MT-2 cell lines. The P2' 4-amino functionality was modified to make a number of amide derivatives to interact with residues in the S2' subsite of the HIV-1 protease active site. Several compounds exhibited picomolar enzyme inhibitory and low nanomolar antiviral activity. The X-ray crystal structure of the chloroacetate derivative bound to HIV-1 protease was determined. Interestingly, the active chloroacetate group converted to the acetate functionality during X-ray exposure. The structure revealed that the P2' carboxamide functionality makes enhanced hydrogen bonding interactions with the backbone atoms in the S2'-subsite.

Keywords: Darunavir; HIV-1 protease; Inhibitor; Synthesis; X-ray structure.

Figure 1.

Structure of protease inhibitors 1-4,

Figure 2.

The X-ray structure of inhibitor 2-bound HIV-1 protease. The inhibitor carbon atoms are shown in turquoise, water molecules are red spheres, and the hydrogen bonds are indicated by dotted lines (PDB ID: 4I8W).

Figure 3.

The X-ray structure of inhibitor 4a-bound HIV-1 protease. The inhibitor carbon atoms are shown in green, water molecules are red spheres, and the hydrogen bonds are indicated by dotted lines (PDB ID: 8F0F).

Scheme 1.

Synthesis of inhibitors 4a-4i.

Scheme 2.

Synthesis of inhibitors 4g-4j.