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针对具有抗拉萨病毒活性的酰腙骨架的先导优化。

Lead optimization of an acylhydrazone scaffold possessing antiviral activity against Lassa virus.

机构信息

SIGA Technologies, Inc., 4575 SW Research Way, Suite 230, Corvallis, OR 97333, United States.

出版信息

Bioorg Med Chem Lett. 2013 Nov 1;23(21):5840-3. doi: 10.1016/j.bmcl.2013.08.103. Epub 2013 Sep 5.

DOI:10.1016/j.bmcl.2013.08.103
PMID:24064500
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC3836667/
Abstract

Previously we reported the optimization of antiviral scaffolds containing benzimidazole and related heterocycles possessing activity against a variety of arenaviruses. These series of compounds were discovered through an HTS campaign of a 400,000 small molecule library using lentivirus-based pseudotypes incorporated with the Lassa virus envelope glycoprotein (LASV GP). This screening also uncovered an alternate series of very potent arenavirus inhibitors based upon an acylhydrazone scaffold. Subsequent SAR analysis of this chemical series involved various substitutions throughout the chemical framework along with assessment of the preferred stereochemistry. These studies led to an optimized analog (ST-161) possessing subnanomolar activity against LASV and submicromolar activity against a number of other viruses in the Arenaviridae family.

摘要

此前，我们报道了含有苯并咪唑和相关杂环的抗病毒支架的优化，这些支架对多种沙粒病毒具有活性。这些化合物系列是通过使用带有拉萨病毒包膜糖蛋白 (LASV GP) 的慢病毒假型对 40 万个小分子文库进行高通量筛选发现的。该筛选还发现了一系列基于酰腙支架的非常有效的沙粒病毒抑制剂。对该化学系列的后续 SAR 分析涉及整个化学结构中的各种取代以及对首选立体化学的评估。这些研究导致了一种优化的类似物 (ST-161)，对 LASV 的活性达到亚纳摩尔级，对 Arenaviridae 家族中的许多其他病毒的活性达到亚微摩尔级。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c02f/3836667/00fa12221a78/nihms522599f3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c02f/3836667/bff794c7be80/nihms522599f1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c02f/3836667/b52e50a15412/nihms522599f2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c02f/3836667/00fa12221a78/nihms522599f3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c02f/3836667/bff794c7be80/nihms522599f1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c02f/3836667/b52e50a15412/nihms522599f2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c02f/3836667/00fa12221a78/nihms522599f3.jpg

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2
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Bioorg Med Chem Lett. 2013 Feb 1;23(3):744-9. doi: 10.1016/j.bmcl.2012.11.095. Epub 2012 Dec 1.
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Design, synthesis, and pharmacological evaluation of N-acylhydrazones and novel conformationally constrained compounds as selective and potent orally active phosphodiesterase-4 inhibitors.
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