Nonpeptidal P₂ Ligands for HIV Protease Inhibitors:  Structure-Based Design, Synthesis, and Biological Evaluation

Abstract

Design and synthesis of nonpeptidal bis-tetrahydrofuran ligands based upon the X-ray crystal structure of the HIV-1 protease-inhibitor complex 1 led to replacement of two amide bonds and a 10 pi-aromatic system of Ro 31-8959 class of HIV protease inhibitors. Detailed structure-activity studies have now established that the position of ring oxygens, ring size, and stereochemistry are all crucial to potency. Of particular interest, compound 49 with (3S,3aS,6aS)-bis-Thf is the most potent inhibitor (IC50 value 1.8 +/- 0.2 nM; CIC95 value 46 +/- 4 nM) in this series. The X-ray structure of protein-inhibitor complex 49 has provided insight into the ligand-binding site interactions. As it turned out, both oxygens in the bis-Thf ligands are involved in hydrogen-bonding interactions with Asp 29 and Asp 30 NH present in the S2 subsite of HIV-1 protease. Stereoselective routes have been developed to obtain these novel ligands in optically pure form.

Probing Lipophilic Adamantyl Group as the P1-Ligand for HIV-1 Protease Inhibitors: Design, Synthesis, Protein X-ray Structural Studies, and Biological Evaluation

“…These azide derivatives were reduced by catalytic hydrogenation over Pd/C under a hydrogen-filled balloon in methanol to provide the amine derivatives 13a–d . 27 This hydrogenation condition also reduced the aromatic nitro group in 12b to the corresponding amine derivative.…”

“…28 (Scheme 3) For the synthesis of respective carbamate derivative, the required activated carbonate derivatives of these ligands 14a–f were prepared as described by us previously. 27, 28 Reaction of amine 13a with succinimidyl carbonate 14a in CH 3 CN at 23 °C for 72 h in the presence of Et 3 N afforded inhibitor 15a in 56% yield. Similarly, other activated carbonate derivatives were reacted with amines 13a–d to provide inhibitors 15b–j in Table 1.…”

Studies of continuous-flow synthesis of nonpeptidal bistetrahydrofuran moiety of Darunavir

“…2 The subsequent radical cyclization produced the bicyclic acetal 3, which was converted to the ketone 4 upon ozonolysis in standard batch reactors.…”

“…2 This reaction with lipase N435 to produce the acetate 6 as a sole product is under investigation and the success in this step can allow to the use of continuous-flow conditions to synthesize the bis-THF 6. Scheme 1: Racemic synthesis, enzymatic resolution route and proposed in the continuous-flow synthesis of bis-THF.…”

Recent Developments of Structure Based β-Secretase Inhibitors for Alzheimers Disease

“…Hydroxyethylamine (HEA) dipeptide isosteres have been widely used as the transition state mimic structures at P 1 -P 1 ' positions in the inhibitors of the aspartyl protease family [36][37][38][39]. Particularly, HEA has been utilized as transition state isostere for the HIV protease inhibitors.…”