Design of HIV-1 Protease Inhibitors with Amino-bis-tetrahydrofuran Derivatives as P2-Ligands to Enhance Backbone-Binding Interactions: Synthesis, Biological Evaluation, and Protein–Ligand X-ray Studies

Abstract

Structure-based design, synthesis, and biological evaluation of a series of very potent HIV-1 protease inhibitors are described. In an effort to improve backbone ligand-binding site interactions, we have incorporated basic-amines at the C4 position of the bis-tetrahydrofuran (bis-THF) ring. We speculated that these substituents would make hydrogen bonding interactions in the flap region of HIV-1 protease. Synthesis of these inhibitors was performed diastereoselectively. A number of inhibitors displayed very potent enzyme inhibitory and antiviral activity. Inhibitors 25f, 25i, and 25j were evaluated against a number of highly-PI-resistant HIV-1 strains and they exhibited improved antiviral activity over darunavir. Two high resolution X-ray structures of 25f and 25g-bound HIV-1 protease revealed unique hydrogen bonding interactions with the backbone carbonyl group of Gly48 as well as with the backbone NH of Gly48 in the flap region of the enzyme active site. These ligand-binding site interactions are possibly responsible for their potent activity.

Novel Protease Inhibitors Containing C-5-Modifiedbis-Tetrahydrofuranylurethane and Aminobenzothiazole as P2 and P2′ Ligands That Exert Potent Antiviral Activity against Highly Multidrug-Resistant HIV-1 with a High Genetic Barrier against the Emergence of Drug Resistance

“…The extreme potency of P2=-Cp-Abt-containing PIs is thought to stem from the favorable van der Waals interactions, in which the Cp-Abt is involved. The formation of hydrogen bonds by the P2 and P2= ligands of PIs with polar groups in S2 and S2= regions of the HIV-1 protease homodimer is thought to be one of the key factors for the much-delayed emergence of drug-resistant HIV-1 variants (37,43). Thus, we further designed, synthesized, and identified three novel PIs (GRL-057-14, GRL-058-14, and GRL-059-14) that contain both a P2-bis-THF moiety carrying the C-5modification and a P2=-Cp-Abt moiety (Fig.…”

“…Such interactions between the inhibitor and the flap main chain are not seen in the interactions of DRV with protease (5). Of note, the present structural model describing the interaction of the C-5-aminoalkyl substituent originated from a crystal structure (PDB identifier [ID] 5BRY), which revealed the presence of water-mediated hydrogen bonds between the protease inhibitor containing THF amine derivative and the Gly48 (37). After careful evaluation of the PDB coordinates (PDB ID 5BRY), we noticed the presence of two water molecules involved in the hydrogen bonding between the C-5-aminoalkyl group and the side chain of Asp29 ( Fig.…”

“…The initial conformation of GRL-057-14 was built in the active site by a structural overlay of similar chemical moieties of GRL-057-14 with the crystal structures of DRV (PDB ID 4HLA) (41), GRL-105-11A (PDB ID 5DGW) (67), and GRL-142 (PDB ID 5TYS) (44). After an initial minimization of GRL-057-14-HIV-1 protease complex using an OPLS3 force field, we used the electron density map of HIV-1 protease structure in complex with GRL-011-11A (PDB ID 5BRY) to further refine the conformation of the C-5 substituent of bis-THF (37). The PDB coordinates and topology file of GRL-057-14 were generated using PRODRG server (68) and manually fitted into an electron density map of GRL-011-11A using Coot (69).…”

Nature Inspired Molecular Design: Stereoselective Synthesis of Bicyclic and Polycyclic Ethers for Potent HIV‐1 Protease Inhibitors

“…[91,92] Indeed, compound 15 (Figure 9) with a C4-isopropylamine functionality showed marked antiviral activity with a 10-fold improvement over darunavir. [91]…”

“…Synthesis of the optically active Boc-protected C-4 isopropylamino bis -THF derivative 105 is shown in Scheme 20. [91] The α,β-unsaturated isopropylidene derivative 98 was synthesized from commercially available D -mannitol as reported. [81] DIBAL- H reduction of 98 provided an allylic alcohol which was reacted with tert -butyl bromoacetate in the presence of cesium hydroxide to afford O -alkylation product 99 .…”