Targeting Fatty Acid Biosynthesis for the Development of Novel Chemotherapeutics against Mycobacterium tuberculosis : Evaluation of A-Ring-Modified Diphenyl Ethers as High-Affinity InhA Inhibitors

Author:

Boyne Melissa E.1,Sullivan Todd J.2,amEnde Christopher W.2,Lu Hao2,Gruppo Veronica1,Heaslip Darragh1,Amin Anita G.1,Chatterjee Delphi1,Lenaerts Anne1,Tonge Peter J.2,Slayden Richard A.31

Affiliation:

1. Department of Microbiology, Immunology and Pathology, Colorado State University, Fort Collins, Colorado 80523-1682

2. Department of Chemistry, Stony Brook University, Stony Brook, New York 11794-3400

3. Rocky Mountain Regional Center of Excellence

Abstract

ABSTRACT Structure-based design was used to develop a focused library of A-ring-modified diphenyl ether InhA inhibitors. From this library of analogs, two high-affinity alkyl-substituted diphenyl ethers, 6PP and 8PP, were selected for advanced study into their in vitro activity against Mycobacterium tuberculosis clinical isolates, their in vivo properties, and their signature response mode of action. 6PP and 8PP demonstrated enhanced activity against whole bacteria and showed activity in a rapid macrophage model of infection. In addition, transcriptional profiling revealed that the A-ring modifications of 6PP and 8PP increased the specificity of each analog for InhA. Both analogs had substantially longer half-lives in serum than did the parent compound, exhibited a fivefold reduction in cytotoxicity compared to the parent compound, and were well tolerated when administered orally at 300 mg/kg of body weight in animal models. Thus, the A-ring modifications increased the affinity and whole-cell specificity of the compounds for InhA and increased their bioavailability. The next step in optimization of the pharmacophore for preclinical evaluation is modification of the B ring to increase the bioavailability to that required for oral delivery.

Publisher

American Society for Microbiology

Subject

Infectious Diseases,Pharmacology (medical),Pharmacology

同舟云学术

1.学者识别学者识别

2.学术分析学术分析

3.人才评估人才评估

"同舟云学术"是以全球学者为主线,采集、加工和组织学术论文而形成的新型学术文献查询和分析系统,可以对全球学者进行文献检索和人才价值评估。用户可以通过关注某些学科领域的顶尖人物而持续追踪该领域的学科进展和研究前沿。经过近期的数据扩容,当前同舟云学术共收录了国内外主流学术期刊6万余种,收集的期刊论文及会议论文总量共计约1.5亿篇,并以每天添加12000余篇中外论文的速度递增。我们也可以为用户提供个性化、定制化的学者数据。欢迎来电咨询!咨询电话:010-8811{复制后删除}0370

www.globalauthorid.com

TOP

Copyright © 2019-2024 北京同舟云网络信息技术有限公司
京公网安备11010802033243号  京ICP备18003416号-3