Novel selective IDO1 inhibitors with isoxazolo[5,4-d]pyrimidin-4(5H)-one scaffold

Dolšak, Ana (author), Bratkovič, Tomaž (author), Mlinarič, Larisa (author), Ogorevc, Eva (author), Švajger, Urban (author), Gobec, Stanislav (author), Sova, Matej (author)

Indoleamine 2,3-dioxygenase 1 (IDO1) is a promising target in immunomodulation of several pathological conditions, especially cancers. Here we present the synthesis of a series of IDO1 inhibitors with the novel isoxazolo[5,4-d]pyrimidin-4(5H)-one scaffold. A focused library was prepared using a 6- or 7-step synthetic procedure to allow a systematic investigation of the structure-activity relationships of the described scaffold. Chemistry-driven modifications lead us to the discovery of our best-in-class inhibitors possessing p-trifluoromethyl (23), p-cyclohexyl (32), or p-methoxycarbonyl (20, 39) substituted aniline moieties with IC$_{50}$ values in the low micromolar range. In addition to hIDO1, compounds were tested for their inhibition of indoleamine 2,3-dioxygenase 2 and tryptophan dioxygenase, and found to be selective for hIDO1. Our results thus demonstrate a successful study on IDO1-selective isoxazolo[5,4-d]pyrimidin-4(5H)-one inhibitors, defining promising chemical probes with a novel scaffold for further development of potent small-molecule immunomodulators.

• Language: English
• Keywords: indoleamine 2, 3-dioxygenase 1, selective inhibitors, isoxazolo[5, 4-d]pyrimidin-4(5H)-one, immunomodulation, cancer
• Work type: Article
• Typology: 1.01 - Original Scientific Article
• Organization: FFA - Faculty of Pharmacy
• Publication status: Published
• Publication version: Version of Record
• Year: 2021
• Number of pages: 18 str.
• Numbering: Vol. 14, iss. 3, art. 265
• PID: 20.500.12556/RUL-135216
• UDC: 616-097+616-006
• ISSN on article: 1424-8247
• DOI: 10.3390/ph14030265
• COBISS.SI-ID: 57316099
• Publication date in RUL: 01.03.2022

Record is a part of a journal

• Title: Pharmaceuticals
• Shortened title: Pharmaceuticals
• Publisher: MDPI
• ISSN: 1424-8247
• COBISS.SI-ID: 517582617

Licences

• License: CC BY 4.0, Creative Commons Attribution 4.0 International
• Link: http://creativecommons.org/licenses/by/4.0/
• Description: This is the standard Creative Commons license that gives others maximum freedom to do what they want with the work as long as they credit the author.
• Licensing start date: 15.03.2021

Secondary language

• Language: Slovenian
• Keywords: selektivni zaviralci, rak, imunomodulacija

Projects

• Funder: ARRS - Slovenian Research Agency
• Project number: P1-0208
• Name: Farmacevtska kemija: načrtovanje, sinteza in vrednotenje učinkovin

• Funder: ARRS - Slovenian Research Agency
• Funding programme: Junior Researcher