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苯骈吡唑酮类化合物抗克氏锥虫的构效关系。

Structure-Activity Relationship of Phenylpyrazolones against Trypanosoma cruzi.

机构信息

Division of Medicinal Chemistry, Faculty of Sciences, Amsterdam Institute for Molecules, Medicines and Systems (AIMMS), Vrije Universiteit Amsterdam, De Boelelaan 1108, 1081 HZ, Amsterdam, The Netherlands.

Laboratory for Microbiology, Parasitology and Hygiene (LMPH), University of Antwerp, Universiteitsplein 1, 2610, Antwerpen, Belgium.

出版信息

ChemMedChem. 2020 Jul 20;15(14):1310-1321. doi: 10.1002/cmdc.202000136. Epub 2020 Apr 27.

DOI:10.1002/cmdc.202000136
PMID:32249532
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC7496920/
Abstract

Chagas disease is a neglected parasitic disease caused by the parasitic protozoan Trypanosoma cruzi and currently affects around 8 million people. Previously, 2-isopropyl-5-(4-methoxy-3-(pyridin-3-yl)phenyl)-4,4-dimethyl-2,4-dihydro-3H-pyrazol-3-one (NPD-0227) was discovered to be a sub-micromolar inhibitor (pIC =6.4) of T. cruzi. So far, SAR investigations of this scaffold have focused on the alkoxy substituent, the pyrazolone nitrogen substituent and the aromatic substituent of the core phenylpyrazolone. In this study, modifications of the phenyldihydropyrazolone scaffold are described. Variations were introduced by installing different substituents on the phenyl core, modifying the geminal dimethyl and installing various bio-isosteres of the dihydropyrazolone group. The anti T. cruzi activity of NPD-0227 could not be surpassed as the most potent compounds show pIC values of around 6.3. However, valuable additional SAR data for this interesting scaffold was obtained, and the data suggest that a scaffold hop is feasible as the pyrazolone moiety can be replaced by a oxazole or oxadiazole with minimal loss of activity.

摘要

恰加斯病是一种被忽视的寄生虫病，由寄生原生动物克氏锥虫引起，目前影响约 800 万人。此前，发现 2-异丙基-5-(4-甲氧基-3-(吡啶-3-基)苯基)-4,4-二甲基-2,4-二氢-3H-吡唑-3-酮（NPD-0227）是克氏锥虫的亚微摩尔抑制剂（pIC =6.4）。到目前为止，对该支架的 SAR 研究主要集中在烷氧基取代基、吡唑酮氮取代基和核心苯吡唑酮的芳基取代基上。在这项研究中，描述了苯并二氢吡唑酮支架的修饰。通过在苯核上安装不同的取代基、修饰偕二甲基以及安装各种二氢吡唑酮基团的生物等排体来引入变化。由于最有效的化合物的 pIC 值约为 6.3，因此无法超过 NPD-0227 的抗 T. cruzi 活性。然而，获得了该有趣支架的有价值的附加 SAR 数据，并且数据表明支架跳跃是可行的，因为吡唑酮部分可以用最小的活性损失被噁唑或噁二唑取代。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/729a/7496920/b46d814019d3/CMDC-15-1310-g012.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/729a/7496920/7f3d3c541c27/CMDC-15-1310-g001.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/729a/7496920/54e4f9e5b3dd/CMDC-15-1310-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/729a/7496920/273a69cdfbef/CMDC-15-1310-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/729a/7496920/c6091cc77dba/CMDC-15-1310-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/729a/7496920/af116f26b359/CMDC-15-1310-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/729a/7496920/3852c23dca46/CMDC-15-1310-g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/729a/7496920/6e46d5f38fd0/CMDC-15-1310-g008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/729a/7496920/00f663ae4392/CMDC-15-1310-g009.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/729a/7496920/92117fd9e44b/CMDC-15-1310-g010.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/729a/7496920/5d745670836e/CMDC-15-1310-g011.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/729a/7496920/b46d814019d3/CMDC-15-1310-g012.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/729a/7496920/7f3d3c541c27/CMDC-15-1310-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/729a/7496920/6d4ff7908cf1/CMDC-15-1310-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/729a/7496920/54e4f9e5b3dd/CMDC-15-1310-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/729a/7496920/273a69cdfbef/CMDC-15-1310-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/729a/7496920/c6091cc77dba/CMDC-15-1310-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/729a/7496920/af116f26b359/CMDC-15-1310-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/729a/7496920/3852c23dca46/CMDC-15-1310-g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/729a/7496920/6e46d5f38fd0/CMDC-15-1310-g008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/729a/7496920/00f663ae4392/CMDC-15-1310-g009.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/729a/7496920/92117fd9e44b/CMDC-15-1310-g010.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/729a/7496920/5d745670836e/CMDC-15-1310-g011.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/729a/7496920/b46d814019d3/CMDC-15-1310-g012.jpg

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