20.500.12556/RUL-135216 Novel selective IDO1 inhibitors with isoxazolo[5,4-d]pyrimidin-4(5H)-one scaffold 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. indoleamine 2 3-dioxygenase 1 selective inhibitors isoxazolo[5 4-d]pyrimidin-4(5H)-one immunomodulation cancer selektivni zaviralci rak imunomodulacija true false true Angleški jezik Slovenski jezik Članek v reviji 2022-03-01 11:51:17 2022-03-01 11:51:22 2022-09-14 04:12:13 0000-00-00 00:00:00 2021 0 0 18 str. iss. 3, art. 265 Vol. 14 2021 0000-00-00 Zaloznikova Objavljeno NiDoloceno 0000-00-00 0000-00-00 0000-00-00 616-097+616-006 1424-8247 10.3390/ph14030265 57316099 RAZ_Dolsak_Ana_2021.pdf RAZ_Dolsak_Ana_2021.pdf 1 179718BB4BA573C878C400A9D3660CCC c38c4704b3703c419134ccc36e0ad723b3fab020714cf65d5dc58e9ea4db16a9 b53966a1-994d-11ec-abdb-00155dcfd717 https://repozitorij.uni-lj.si/Dokument.php?lang=slv&id=154142 https://www.mdpi.com/1424-8247/14/3/265 1 44b6fa98-994d-11ec-abdb-00155dcfd717 https://repozitorij.uni-lj.si/Dokument.php?lang=slv&id=154141 Fakulteta za farmacijo 0 0 0