Synthesis of Selenoesters via Aldol Condensation and/or Conjugate Reduction and Their Antiviral Activities

A variety of unsaturated selenoesters (including phenolic ones) were produced in good to high yields and with high E/Z ratios using TiCl4-promoted aldol condensation between Se-phenyl selenoacetate and their respective aldehydes without aqueous workup. A representative phenolic unsaturated selenoester was applied to acylation of tyrosine methyl ester without protection of the phenolic hydroxy groups to furnish the corresponding amino acid conjugate. The conjugate reduction of the unsaturated selenoesters including phenolic ones and selenocoumarin with HSiEt3 was catalyzed by B(C6F5)3 to afford the corresponding saturated selenoesters in good to high yields. This method was also applicable to the reduction of a saturated selenoester to the corresponding O-silyl hemiselenoacetal in a high yield. Moreover, most acyclic unsaturated selenoesters were found to show good multiple antiviral activities against HIV-1, HBV, and SARS-CoV-2

Design and Synthesis of Potent HIV-1 Protease Inhibitors Incorporating Hexahydrofuropyranol-Derived High Affinity P₂ Ligands: Structure−Activity Studies and Biological Evaluation

The design, synthesis, and evaluation of a new series of hexahydrofuropyranol-derived HIV-1 protease inhibitors are described. We have designed a stereochemically defined hexahydrofuropyranol-derived urethane as the P2-ligand. The current ligand is designed based upon the X-ray structure of 1a-bound HIV-1 protease. The synthesis of (3aS,4S,7aR)-hexahydro-2H-furo[2,3-b]pyran-4-ol, (−)-7, was carried out in optically active form. Incorporation of this ligand provided inhibitor 35a, which has shown excellent enzyme inhibitory activity and antiviral potency. Our structure−activity studies have indicated that the stereochemistry and the position of oxygens in the ligand are important to the observed potency of the inhibitor. Inhibitor 35a has maintained excellent potency against multidrug-resistant HIV-1 variants. An active site model of 35a was created based upon the X-ray structure of 1b-bound HIV-1 protease. The model offers molecular insights regarding ligand-binding site interactions of the hexahydrofuropyranol-derived novel P2-ligand

Design, Synthesis, and X-ray Structure of Substituted Bis-tetrahydrofuran (Bis-THF)-Derived Potent HIV-1 Protease Inhibitors

We investigated substituted bis-THF-derived HIV-1 protease inhibitors in order to enhance ligand-binding site interactions in the HIV-1 protease active site. In this context, we have carried out convenient syntheses of optically active bis-THF and C4-substituted bis-THF ligands using a [2,3]-sigmatropic rearrangement as the key step. The synthesis provided convenient access to a number of substituted bis-THF derivatives. Incorporation of these ligands led to a series of potent HIV-1 protease inhibitors. Inhibitor 23c turned out to be the most potent (Ki = 2.9 pM; IC50 = 2.4 nM) among the inhibitors. An X-ray structure of 23c-bound HIV-1 protease showed extensive interactions of the inhibitor with the protease active site, including a unique water-mediated hydrogen bond to the Gly-48 amide NH in the S2 site

Structure-Based Design of Potent HIV‑1 Protease Inhibitors with Modified P1-Biphenyl Ligands: Synthesis, Biological Evaluation, and Enzyme–Inhibitor X‑ray Structural Studies

We report the design, synthesis, X-ray structural studies, and biological evaluation of a novel series of HIV-1 protease inhibitors. We designed a variety of functionalized biphenyl derivatives to make enhanced van der Waals interactions in the S1 subsite of HIV-1 protease. These biphenyl derivatives were conveniently synthesized using a Suzuki–Miyaura cross-coupling reaction as the key step. We examined the potential of these functionalized biphenyl-derived P1 ligands in combination with 3-(<i>S</i>)-tetrahydrofuranyl urethane and bis-tetrahydrofuranyl urethane as the P2 ligands. Inhibitor <b>21e</b>, with a 2-methoxy-1,1′-biphenyl derivative as P1 ligand and bis-THF as the P2 ligand, displayed the most potent enzyme inhibitory and antiviral activity. This inhibitor also exhibited potent activity against a panel of multidrug-resistant HIV-1 variants. A high resolution X-ray crystal structure of related Boc-derivative <b>17a</b>-bound HIV-1 protease provided important molecular insight into the ligand-binding site interactions of the biphenyl core in the S1 subsite of HIV-1 protease

Design of HIV-1 Protease Inhibitors with C3-Substituted Hexahydrocyclopentafuranyl Urethanes as P2-Ligands: Synthesis, Biological Evaluation, and Protein–Ligand X-ray Crystal Structure

We report the design, synthesis, biological evaluation, and the X-ray crystal structure of a novel inhibitor bound to the HIV-1 protease. Various C3-functionalized cyclopentanyltetrahydrofurans (Cp-THF) were designed to interact with the flap Gly48 carbonyl or amide NH in the S2-subsite of the HIV-1 protease. We investigated the potential of those functionalized ligands in combination with hydroxyethylsulfonamide isosteres. Inhibitor 26 containing a 3-(R)-hydroxyl group on the Cp-THF core displayed the most potent enzyme inhibitory and antiviral activity. Our studies revealed a preference for the 3-(R)-configuration over the corresponding 3-(S)-derivative. Inhibitor 26 exhibited potent activity against a panel of multidrug-resistant HIV-1 variants. A high resolution X-ray structure of 26-bound HIV-1 protease revealed important molecular insight into the ligand-binding site interactions

Highly Potent HIV‑1 Protease Inhibitors with Novel Tricyclic P2 Ligands: Design, Synthesis, and Protein–Ligand X‑ray Studies

The design, synthesis, and biological evaluation of a series of HIV-1 protease inhibitors incorporating stereochemically defined fused tricyclic P2 ligands are described. Various substituent effects were investigated to maximize the ligand-binding site interactions in the protease active site. Inhibitors <b>16a</b> and <b>16f</b> showed excellent enzyme inhibitory and antiviral activity, although the incorporation of sulfone functionality resulted in a decrease in potency. Both inhibitors <b>16a</b> and <b>16f</b> maintained activity against a panel of multidrug resistant HIV-1 variants. A high-resolution X-ray crystal structure of <b>16a</b>-bound HIV-1 protease revealed important molecular insights into the ligand-binding site interactions, which may account for the inhibitor’s potent antiviral activity and excellent resistance profiles

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 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, Synthesis, Protein−Ligand X-ray Structure, and Biological Evaluation of a Series of Novel Macrocyclic Human Immunodeficiency Virus-1 Protease Inhibitors to Combat Drug Resistance

The structure-based design, synthesis, and biological evaluation of a series of nonpeptidic macrocyclic HIV protease inhibitors are described. The inhibitors are designed to effectively fill in the hydrophobic pocket in the S1′−S2′ subsites and retain all major hydrogen bonding interactions with the protein backbone similar to darunavir (1) or inhibitor 2. The ring size, the effect of methyl substitution, and unsaturation within the macrocyclic ring structure were assessed. In general, cyclic inhibitors were significantly more potent than their acyclic homologues, saturated rings were less active than their unsaturated analogues and a preference for 10- and 13-membered macrocylic rings was revealed. The addition of methyl substituents resulted in a reduction of potency. Both inhibitors 14b and 14c exhibited marked enzyme inhibitory and antiviral activity, and they exerted potent activity against multidrug-resistant HIV-1 variants. Protein−ligand X-ray structures of inhibitors 2 and 14c provided critical molecular insights into the ligand-binding site interactions