Allosteric Inhibitors against HIV-1 Reverse Transcriptase: Design and Synthesis of MKC-442 Analogues Having an Ω-Functionalized Acyclic Structure-Reference-Cited by-同舟云学术

Allosteric Inhibitors against HIV-1 Reverse Transcriptase: Design and Synthesis of MKC-442 Analogues Having an Ω-Functionalized Acyclic Structure

Published:1998-08 Issue:4 Volume:9 Page:41-48
ISSN:2040-2066
Container-title:Antiviral Chemistry and Chemotherapy
language:en
Short-container-title:Antivir Chem Chemother

Author:

Tanaka H¹,Walker RT²,Hopkins AL³,Ren J³,Jones EY³⁴,Fujimoto K¹,Hayashi M¹,Miyasaka T¹,Baba M⁵,Stammers DK³,Stuart DI³⁴

Affiliation:

1. School of Pharmaceutical Sciences, Showa University, 1-5-8 Hatanodai, Shinagawa-ku, Tokyo 142, Japan

2. School of Chemistry, The University of Birmingham, Edgbaston, Birmingham B15 2TT, UK

3. The Laboratory of Molecular Biophysics, Rex Richards Building, South Parks Road, Oxford OX1 3QU, UK

4. The Oxford Centre for Molecular Sciences, New Chemistry Building, South Parks Road, Oxford OX1 3QT, UK

5. Division of Human Retroviruses, Center for Chronic Viral Diseases, Faculty of Medicine, Kagoshima University, Kagoshima 890, Japan

Abstract

Based on X-ray crystallographic analysis of MKC-442/human immunodeficiency virus type 1 reverse transcriptase (HIV-1 RT) complex, analogues in which the N1-substituent is replaced with ω-functionalized alkyl groups were designed to improve the affinity for the enzyme. Synthesis of these compounds was carried out starting from MKC-442 by a sequence of reactions (N3-protection, removal of N1-ethoxymethyl group, alkylation, and N3-deprotection). The compounds were evaluated for anti-HIV activity. Structure–activity relationships are discussed in terms of the possible interaction with the enzyme.

Publisher

SAGE Publications

Link

http://journals.sagepub.com/doi/pdf/10.1177/095632029800900404

Reference18 articles.

1. Highly specific inhibition of human immunodeficiency virus type 1 by a novel 6-substituted acyclouridine derivative

2. Preclinical evaluation of MKC-442, a highly potent and specific inhibitor of human immunodeficiency virus type 1 in vitro

3. The inhibition of human immunodeficiency virus type 1 in vitro by a non-nucleoside reverse transcriptase inhibitor MKC-442, alone and in combination with other anti-HIV compounds

4. Non-nucleoside reverse transcriptase inhibitors (NNRTIs) for the treatment of human immunodeficiency virus type 1 (HIV-1) infections: Strategies to overcome drug resistance development

5. Unique features in the structure of the complex between HIV-1 reverse transcriptase and the bis(heteroaryl)piperazine (BHAP) U-90152 explain resistance mutations for this nonnucleoside inhibitor

Cited by 7 articles. 订阅此论文施引文献订阅此论文施引文献，注册后可以免费订阅5篇论文的施引文献，订阅后可以查看论文全部施引文献

1. 6-(Arylmethyl)pyrimidin-4(3H)-ones: anthology and prospects of highly efficient anti-HIV agents;Russian Chemical Bulletin;2012-07

2. Allosteric Proteins and Drug Discovery;Burger's Medicinal Chemistry and Drug Discovery;2010-09-15

3. Design of Non-Nucleoside Inhibitors of HIV-1 Reverse Transcriptase with Improved Drug Resistance Properties. 1.;Journal of Medicinal Chemistry;2004-10-23

4. Nucleoside Analogues Exerting Antiviral Activity Through a Non‐nucleoside Mechanism;Nucleosides, Nucleotides & Nucleic Acids;2004-01-01

5. Allosteric Proteins and Drug Discovery;Burger's Medicinal Chemistry and Drug Discovery;2003-01-15