涉及P1 - P2配体的强效大环HIV - 1蛋白酶抑制剂的设计与合成。
Design and synthesis of potent macrocyclic HIV-1 protease inhibitors involving P1-P2 ligands.
作者信息
Ghosh Arun K, Schiltz Gary E, Rusere Linah N, Osswald Heather L, Walters D Eric, Amano Masayuki, Mitsuya Hiroaki
机构信息
Departments of Chemistry and Medicinal Chemistry, Purdue University, West Lafayette, IN 47907, USA.
出版信息
Org Biomol Chem. 2014 Sep 21;12(35):6842-54. doi: 10.1039/c4ob00738g.
Abstract
A series of potent macrocyclic HIV-1 protease inhibitors have been designed and synthesized. The compounds incorporated 16- to 19-membered macrocyclic rings between a nelfinavir-like P2 ligand and a tyrosine side chain containing a hydroxyethylamine sulfonamide isostere. All cyclic inhibitors are more potent than their corresponding acyclic counterparts. Saturated derivatives showed slight reduction of potency compared to the respective unsaturated derivatives. Compound containing a 16-membered ring as the P1-P2 ligand showed the most potent enzyme inhibitory and antiviral activity.
摘要
一系列强效的大环HIV-1蛋白酶抑制剂已被设计并合成。这些化合物在奈非那韦样P2配体和含有羟乙胺磺酰胺等排体的酪氨酸侧链之间引入了16至19元大环。所有环状抑制剂都比其相应的非环状类似物更有效。与各自的不饱和衍生物相比，饱和衍生物的效力略有降低。含有16元环作为P1-P2配体的化合物表现出最有效的酶抑制和抗病毒活性。
相似文献
1
Design and synthesis of potent macrocyclic HIV-1 protease inhibitors involving P1-P2 ligands.涉及P1 - P2配体的强效大环HIV - 1蛋白酶抑制剂的设计与合成。
Org Biomol Chem. 2014 Sep 21;12(35):6842-54. doi: 10.1039/c4ob00738g.
2
Structure-based design: synthesis and biological evaluation of a series of novel cycloamide-derived HIV-1 protease inhibitors.基于结构的设计：一系列新型环酰胺衍生的HIV-1蛋白酶抑制剂的合成与生物学评价
J Med Chem. 2005 May 19;48(10):3576-85. doi: 10.1021/jm050019i.
3
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.含三环稠合环系作为新型 P2 配体的高效抗 HIV-1 蛋白酶抑制剂的设计与合成：构效关系研究、生物学及 X 射线结构分析。
J Med Chem. 2018 May 24;61(10):4561-4577. doi: 10.1021/acs.jmedchem.8b00298. Epub 2018 May 15.
4
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.一系列用于对抗耐药性的新型大环人类免疫缺陷病毒-1蛋白酶抑制剂的设计、合成、蛋白质-配体X射线结构及生物学评价
J Med Chem. 2009 Dec 10;52(23):7689-705. doi: 10.1021/jm900695w.
5
Piperidine scaffold as the novel P2-ligands in cyclopropyl-containing HIV-1 protease inhibitors: Structure-based design, synthesis, biological evaluation and docking study.哌啶骨架作为新型含环丙基 HIV-1 蛋白酶抑制剂的 P2 配体：基于结构的设计、合成、生物评价及对接研究。
PLoS One. 2020 Jul 22;15(7):e0235483. doi: 10.1371/journal.pone.0235483. eCollection 2020.
6
Structure-based design of novel HIV-1 protease inhibitors to combat drug resistance.基于结构设计新型HIV-1蛋白酶抑制剂以对抗耐药性。
J Med Chem. 2006 Aug 24;49(17):5252-61. doi: 10.1021/jm060561m.
7
Design and synthesis of potent HIV-1 protease inhibitors incorporating hydroxyprolinamides as novel P2 ligands.设计并合成了强效的 HIV-1 蛋白酶抑制剂，其中包含羟脯氨酰胺作为新型 P2 配体。
Bioorg Med Chem Lett. 2011 Jun 15;21(12):3730-3. doi: 10.1016/j.bmcl.2011.04.070. Epub 2011 Apr 24.
8
Structure-based design of potent HIV-1 protease inhibitors with modified P1-biphenyl ligands: synthesis, biological evaluation, and enzyme-inhibitor X-ray structural studies.基于结构设计具有修饰的P1-联苯配体的强效HIV-1蛋白酶抑制剂：合成、生物学评价及酶-抑制剂X射线结构研究
J Med Chem. 2015 Jul 9;58(13):5334-43. doi: 10.1021/acs.jmedchem.5b00676. Epub 2015 Jun 24.
9
Flexible cyclic ethers/polyethers as novel P2-ligands for HIV-1 protease inhibitors: design, synthesis, biological evaluation, and protein-ligand X-ray studies.柔性环状醚/聚醚作为新型HIV-1蛋白酶抑制剂的P2配体：设计、合成、生物学评价及蛋白质-配体X射线研究
J Med Chem. 2008 Oct 9;51(19):6021-33. doi: 10.1021/jm8004543. Epub 2008 Sep 11.
10
Rational design, synthesis and biological evaluation of novel HIV-1 protease inhibitors containing 2-phenylacetamide derivatives as P2 ligands with potent activity against DRV-Resistant HIV-1 variants.新型 HIV-1 蛋白酶抑制剂的合理设计、合成与生物评价，该抑制剂含有作为 P2 配体的 2-苯乙酰胺衍生物，对 DRV 耐药的 HIV-1 变异体具有很强的抑制活性。
Bioorg Med Chem Lett. 2024 Mar 15;101:129651. doi: 10.1016/j.bmcl.2024.129651. Epub 2024 Feb 9.
引用本文的文献
1
Beyond darunavir: recent development of next generation HIV-1 protease inhibitors to combat drug resistance.超越达芦那韦：新一代 HIV-1 蛋白酶抑制剂抵抗耐药性的最新进展。
Chem Commun (Camb). 2022 Oct 20;58(84):11762-11782. doi: 10.1039/d2cc04541a.
2
Design, synthesis, and X-ray studies of potent HIV-1 protease inhibitors incorporating aminothiochromane and aminotetrahydronaphthalene carboxamide derivatives as the P2 ligands.设计、合成及 X 射线研究强效 HIV-1 蛋白酶抑制剂，其中包含作为 P2 配体的氨基噻吩并[2,3-d]嘧啶和氨基四氢萘甲酰胺衍生物。
Eur J Med Chem. 2018 Dec 5;160:171-182. doi: 10.1016/j.ejmech.2018.09.046. Epub 2018 Sep 18.
3
Design, synthesis, X-ray studies, and biological evaluation of novel macrocyclic HIV-1 protease inhibitors involving the P1'-P2' ligands.涉及P1'-P2'配体的新型大环HIV-1蛋白酶抑制剂的设计、合成、X射线研究及生物学评价
Bioorg Med Chem Lett. 2017 Nov 1;27(21):4925-4931. doi: 10.1016/j.bmcl.2017.09.003. Epub 2017 Sep 6.
4
Design of novel HIV-1 protease inhibitors incorporating isophthalamide-derived P2-P3 ligands: Synthesis, biological evaluation and X-ray structural studies of inhibitor-HIV-1 protease complex.新型HIV-1蛋白酶抑制剂的设计：引入间苯二甲酰胺衍生的P2-P3配体、抑制剂-HIV-1蛋白酶复合物的合成、生物学评价及X射线结构研究
Bioorg Med Chem. 2017 Oct 1;25(19):5114-5127. doi: 10.1016/j.bmc.2017.04.005. Epub 2017 Apr 9.
5
Design and Development of Highly Potent HIV-1 Protease Inhibitors with a Crown-Like Oxotricyclic Core as the P2-Ligand To Combat Multidrug-Resistant HIV Variants.以冠状氧三环核心作为P2配体设计和开发高效HIV-1蛋白酶抑制剂以对抗多药耐药HIV变体
J Med Chem. 2017 May 25;60(10):4267-4278. doi: 10.1021/acs.jmedchem.7b00172. Epub 2017 Apr 18.
6
Recent Progress in the Development of HIV-1 Protease Inhibitors for the Treatment of HIV/AIDS.用于治疗艾滋病毒/艾滋病的HIV-1蛋白酶抑制剂开发的最新进展
J Med Chem. 2016 Jun 9;59(11):5172-208. doi: 10.1021/acs.jmedchem.5b01697. Epub 2016 Jan 22.
7
Structure-based design, synthesis, X-ray studies, and biological evaluation of novel HIV-1 protease inhibitors containing isophthalamide-derived P2-ligands.基于结构的新型含间苯二甲酰胺衍生P2配体的HIV-1蛋白酶抑制剂的设计、合成、X射线研究及生物学评价
Bioorg Med Chem Lett. 2015 Nov 1;25(21):4903-4909. doi: 10.1016/j.bmcl.2015.05.052. Epub 2015 May 30.
8
Study of the antimalarial properties of hydroxyethylamine derivatives using green fluorescent protein transformed Plasmodium berghei.利用绿色荧光蛋白转化的伯氏疟原虫研究羟乙胺衍生物的抗疟特性。
Mem Inst Oswaldo Cruz. 2015 Jun;110(4):560-5. doi: 10.1590/0074-02760140466. Epub 2015 May 26.
本文引用的文献
1
A Facile and Enantiospecific Synthesis of 2()- and 2()-[1'()-Azido-2-phenylethyl]oxirane.2()-和2()-[1'()-叠氮基-2-苯乙基]环氧乙烷的简便对映体特异性合成
J Chem Soc Chem Commun. 1992;1992(3):273-274. doi: 10.1039/C39920000273.
2
Enhancing protein backbone binding--a fruitful concept for combating drug-resistant HIV.增强蛋白主链结合——一种有前途的对抗耐药性 HIV 的概念。
Angew Chem Int Ed Engl. 2012 Feb 20;51(8):1778-802. doi: 10.1002/anie.201102762. Epub 2012 Jan 31.
3
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.一系列用于对抗耐药性的新型大环人类免疫缺陷病毒-1蛋白酶抑制剂的设计、合成、蛋白质-配体X射线结构及生物学评价
J Med Chem. 2009 Dec 10;52(23):7689-705. doi: 10.1021/jm900695w.
4
Demonstration of sustained drug-resistant human immunodeficiency virus type 1 lineages circulating among treatment-naïve individuals.初治个体中持续存在的耐药1型人类免疫缺陷病毒谱系的证明。
J Virol. 2009 Mar;83(6):2645-54. doi: 10.1128/JVI.01556-08. Epub 2009 Jan 21.
5
Emergence of drug resistance in HIV type 1-infected patients after receipt of first-line highly active antiretroviral therapy: a systematic review of clinical trials.1型人类免疫缺陷病毒感染患者接受一线高效抗逆转录病毒治疗后耐药性的出现：一项临床试验的系统评价
Clin Infect Dis. 2008 Sep 1;47(5):712-22. doi: 10.1086/590943.
6
Molecular analysis of the HIV-1 resistance development: enzymatic activities, crystal structures, and thermodynamics of nelfinavir-resistant HIV protease mutants.HIV-1耐药性发展的分子分析：奈非那韦耐药HIV蛋白酶突变体的酶活性、晶体结构和热力学
J Mol Biol. 2007 Dec 7;374(4):1005-16. doi: 10.1016/j.jmb.2007.09.083. Epub 2007 Oct 3.
7
Darunavir, a conceptually new HIV-1 protease inhibitor for the treatment of drug-resistant HIV.达芦那韦，一种从概念上来说全新的用于治疗耐药性艾滋病毒的HIV-1蛋白酶抑制剂。
Bioorg Med Chem. 2007 Dec 15;15(24):7576-80. doi: 10.1016/j.bmc.2007.09.010. Epub 2007 Sep 14.
8
Design of HIV protease inhibitors targeting protein backbone: an effective strategy for combating drug resistance.靶向蛋白质主链的HIV蛋白酶抑制剂设计：一种对抗耐药性的有效策略。
Acc Chem Res. 2008 Jan;41(1):78-86. doi: 10.1021/ar7001232. Epub 2007 Aug 28.
9
A novel bis-tetrahydrofuranylurethane-containing nonpeptidic protease inhibitor (PI), GRL-98065, is potent against multiple-PI-resistant human immunodeficiency virus in vitro.一种新型含双四氢呋喃基聚氨酯的非肽类蛋白酶抑制剂（PI）GRL-98065，在体外对多种耐PI的人类免疫缺陷病毒具有强效作用。
Antimicrob Agents Chemother. 2007 Jun;51(6):2143-55. doi: 10.1128/AAC.01413-06. Epub 2007 Mar 19.
10
Structure-based design of novel HIV-1 protease inhibitors to combat drug resistance.基于结构设计新型HIV-1蛋白酶抑制剂以对抗耐药性。
J Med Chem. 2006 Aug 24;49(17):5252-61. doi: 10.1021/jm060561m.
Zotero 插件