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

A series of potent HIV-1 protease inhibitors with a lipophilic adamantyl P1 ligand have been designed, synthesized, and evaluated. We have developed an enantioselective synthesis of adamantane-derived hydroxyethylamine isosteres utilizing Sharpless asymmetric epoxidation as the key step. Various inhibitors incorporating P1-adamantylmethyl in combination with P2 ligands such as 3-(<i>R</i>)-THF, 3-(<i>S</i>)-THF, bis-THF, and THF-THP were examined. The S1′ pocket was also probed with phenyl and phenylmethyl ligands. Inhibitor <b>15d</b>, with an isobutyl P1′ ligand and a bis-THF P2 ligand, proved to be the most potent of the series. The cLogP value of inhibitor <b>15d</b> is improved compared to inhibitor <b>2</b> with a phenylmethyl P1-ligand. X-ray structural studies of <b>15d</b>, <b>15h</b>, and <b>15i</b> with HIV-1 protease complexes revealed molecular insight into the inhibitor–protein interaction

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

A series of potent HIV-1 protease inhibitors with a lipophilic adamantyl P1 ligand have been designed, synthesized, and evaluated. We have developed an enantioselective synthesis of adamantane-derived hydroxyethylamine isosteres utilizing Sharpless asymmetric epoxidation as the key step. Various inhibitors incorporating P1-adamantylmethyl in combination with P2 ligands such as 3-(<i>R</i>)-THF, 3-(<i>S</i>)-THF, bis-THF, and THF-THP were examined. The S1′ pocket was also probed with phenyl and phenylmethyl ligands. Inhibitor <b>15d</b>, with an isobutyl P1′ ligand and a bis-THF P2 ligand, proved to be the most potent of the series. The cLogP value of inhibitor <b>15d</b> is improved compared to inhibitor <b>2</b> with a phenylmethyl P1-ligand. X-ray structural studies of <b>15d</b>, <b>15h</b>, and <b>15i</b> with HIV-1 protease complexes revealed molecular insight into the inhibitor–protein interaction

Reduction of Peptide Character of HIV Protease Inhibitors That Exhibit Nanomolar Potency against Multidrug Resistant HIV-1 Strains

Novel HIV protease inhibitors containing a hydroxyethylamine dipeptide isostere as a transition state-mimic king structure were synthesized by combining substructures of known HIV protease inhibitors. Among them, TYA5 and TYB5 were proven to be not only potent enzyme inhibitors (Ki = 0.12 nM and 0.10 nM, respectively) but also strong anti-HIV agents (IC50 = 9.5 nM and 66 nM, respectively), even against viral strains with multidrug resistance. Furthermore, insertion of an (E)-alkene dipeptide isostere at the P1−P2 position of TYB5 led to development of a purely nonpeptidic protease inhibitor, TYB1 (Ki = 0.38 nM, IC50 = 160 nM)

Reduction of Peptide Character of HIV Protease Inhibitors That Exhibit Nanomolar Potency against Multidrug Resistant HIV-1 Strains

Novel HIV protease inhibitors containing a hydroxyethylamine dipeptide isostere as a transition state-mimic king structure were synthesized by combining substructures of known HIV protease inhibitors. Among them, TYA5 and TYB5 were proven to be not only potent enzyme inhibitors (Ki = 0.12 nM and 0.10 nM, respectively) but also strong anti-HIV agents (IC50 = 9.5 nM and 66 nM, respectively), even against viral strains with multidrug resistance. Furthermore, insertion of an (E)-alkene dipeptide isostere at the P1−P2 position of TYB5 led to development of a purely nonpeptidic protease inhibitor, TYB1 (Ki = 0.38 nM, IC50 = 160 nM)

Design and Synthesis of Highly Potent HIV‑1 Protease Inhibitors Containing Tricyclic Fused Ring Systems as Novel P2 Ligands: Structure–Activity Studies, Biological and X‑ray Structural Analysis

The design, synthesis, and biological evaluation of a new class of HIV-1 protease inhibitors containing stereochemically defined fused tricyclic polyethers as the P2 ligands and a variety of sulfonamide derivatives as the P2′ ligands are described. A number of ring sizes and various substituent effects were investigated to enhance the ligand–backbone interactions in the protease active site. Inhibitors <b>5c</b> and <b>5d</b> containing this unprecedented fused 6–5–5 ring system as the P2 ligand, an aminobenzothiazole as the P2′ ligand, and a difluorophenylmethyl as the P1 ligand exhibited exceptional enzyme inhibitory potency and maintained excellent antiviral activity against a panel of highly multidrug-resistant HIV-1 variants. The umbrella-like P2 ligand for these inhibitors has been synthesized efficiently in an optically active form using a Pauson–Khand cyclization reaction as the key step. The racemic alcohols were resolved efficiently using a lipase catalyzed enzymatic resolution. Two high resolution X-ray structures of inhibitor-bound HIV-1 protease revealed extensive interactions with the backbone atoms of HIV-1 protease and provided molecular insight into the binding properties of these new inhibitors

Diastereoselective Synthesis of 6″‑(<i>Z</i>)- and 6″‑(<i>E</i>)‑Fluoro Analogues of Anti-hepatitis B Virus Agent Entecavir and Its Evaluation of the Activity and Toxicity Profile of the Diastereomers

A method for the diastereoselective synthesis of 6″-(<i>Z</i>)- and 6″‑(<i>E</i>)-fluorinated analogues of the anti-HBV agent entecavir has been developed. Construction of the methylenecyclopentane skeleton of the target molecules has been accomplished by radical-mediated 5-<i>exo</i>-<i>dig</i> cyclization of the selenides <b>6</b> and <b>15</b> having the phenylsulfanylethynyl structure as a radical accepting moiety. In the radical reaction of the TBS-protected precursor <b>6</b>, (<i>Z</i>)-<i>anti</i>-<b>12</b> was formed as a major product. On the other hand, TIPS-protected <b>15</b> gave (<i>E</i>)-<i>anti</i>-<b>12</b>. The sulfur-extrusive stannylation of <i>anti</i>-<b>12</b> furnished a mixture of geometric isomers of the respective vinylstannane, whereas benzoyl-protected <b>17</b> underwent the stannylation in the manner of retention of configuration. Following XeF₂-mediated fluorination, introduction of the purine base and deoxygenation of the resulting carbocyclic guanosine gave the target (<i>E</i>)- and (<i>Z</i>)-<b>3</b> after deprotection. Evaluation of the anti-HBV activity of <b>3</b> revealed that fluorine-substitution at the 6″-position of entecavir gave rise to a reduction in the cytotoxicity in HepG2 cells with retention of the antiviral activity

Design and Synthesis of Highly Potent HIV‑1 Protease Inhibitors Containing Tricyclic Fused Ring Systems as Novel P2 Ligands: Structure–Activity Studies, Biological and X‑ray Structural Analysis

The design, synthesis, and biological evaluation of a new class of HIV-1 protease inhibitors containing stereochemically defined fused tricyclic polyethers as the P2 ligands and a variety of sulfonamide derivatives as the P2′ ligands are described. A number of ring sizes and various substituent effects were investigated to enhance the ligand–backbone interactions in the protease active site. Inhibitors <b>5c</b> and <b>5d</b> containing this unprecedented fused 6–5–5 ring system as the P2 ligand, an aminobenzothiazole as the P2′ ligand, and a difluorophenylmethyl as the P1 ligand exhibited exceptional enzyme inhibitory potency and maintained excellent antiviral activity against a panel of highly multidrug-resistant HIV-1 variants. The umbrella-like P2 ligand for these inhibitors has been synthesized efficiently in an optically active form using a Pauson–Khand cyclization reaction as the key step. The racemic alcohols were resolved efficiently using a lipase catalyzed enzymatic resolution. Two high resolution X-ray structures of inhibitor-bound HIV-1 protease revealed extensive interactions with the backbone atoms of HIV-1 protease and provided molecular insight into the binding properties of these new inhibitors

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

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 <b>25f</b>, <b>25i</b>, and <b>25j</b> 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 <b>25f</b>- and <b>25g</b>-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