Design, Synthesis and X-ray Structural Studies of Potent HIV-1 Protease Inhibitors Containing C-4 Substituted Tricyclic Hexahydro-furofuran Derivatives as P2 Ligands

被引：5

作者：

Ghosh, Arun K. ^{[1
,2
]}

Kovela, Satish ^{[1
,2
]}

Sharma, Ashish ^{[1
,2
]}

Shahabi, Dana ^{[1
,2
]}

Ghosh, Ajay K. ^{[1
,2
]}

Hopkins, Denver R. ^{[1
,2
]}

Yadav, Monika ^{[1
,2
]}

Johnson, Megan E. ^{[1
,2
]}

Agniswamy, Johnson ^{[3
,4
]}

Wang, Yuan-Fang ^{[3
,4
]}

Hattori, Shin-Ichiro ^{[5
]}

Higashi-Kuwata, Nobuyo ^{[5
]}

Aoki, Manabu ^{[6
,7
]}

Amano, Masayuki ^{[6
,7
]}

Weber, Irene T. ^{[3
,4
]}

Mitsuya, Hiroaki ^{[6
,7
,8
,9
,10
]}

机构：

[1] Purdue Univ, Dept Chem, W Lafayette, IN 47907 USA

[2] Purdue Univ, Dept Med Chem, W Lafayette, IN 47907 USA

[3] Georgia State Univ, Dept Biol, Atlanta, GA 30303 USA

[4] Georgia State Univ, Dept Chem, Mol Basis Dis, Atlanta, GA 30303 USA

[5] Natl Ctr Global Hlth & Med, Dept Refractory Viral Infect, Res Inst, Shinjuku Ku, Tokyo 1628655, Japan

[6] Kumamoto Univ, Sch Med, Dept Hematol, Kumamoto 8608556, Japan

[7] Kumamoto Univ, Sch Med, Dept Infect Dis, Kumamoto 8608556, Japan

[8] NCI, Expt Retrovirol Sect, HIV & AIDS Malignancy Branch, Bethesda, MD 20892 USA

[9] Natl Ctr Global Heath & Med, Ctr Clin Sci, Shinjuku Ku, Tokyo 1628655, Japan

[10] Natl Ctr Global Hlth & Med, Dept Refractory Viral Infect, Shinjuku Ku, Tokyo 1628655, Japan

来源：

CHEMMEDCHEM | 2022年 / 17卷 / 09期

基金：

美国国家卫生研究院;

关键词：

antiviral agents; backbone binding; HIV-1; protease; inhibitors; multidrug-resistance; BIS-THF MOIETIES; ANTIRETROVIRAL THERAPY; CCP4; SUITE; RESISTANT; DARUNAVIR; BINDING; P2-LIGAND; SELECTION; STRATEGY; BACKBONE;

D O I：

10.1002/cmdc.202200058

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

The design, synthesis, X-ray structural, and biological evaluation of a series of highly potent HIV-1 protease inhibitors are reported herein. These inhibitors incorporate novel cyclohexane-fused tricyclic bis-tetrahydrofuran as P2 ligands in combination with a variety of P1 and P2 ' ligands. The inhibitor with a difluoromethylphenyl P1 ligand and a cyclopropylaminobenzothiazole P2 ' ligand exhibited the most potent antiviral activity. Also, it maintained potent antiviral activity against a panel of highly multidrug-resistant HIV-1 variants. The corresponding inhibitor with an enantiomeric ligand was significantly less potent in these antiviral assays. The new P2 ligands were synthesized in optically active form using enzymatic desymmetrization of meso-diols as the key step. To obtain molecular insight, two high-resolution X-ray structures of inhibitor-bound HIV-1 protease were determined and structural analyses have been highlighted.

引用

页数：12