Abstract
AbstractThe histone deacetylases (HDACs) are being explored as a promising therapeutic target for the treatment of various diseases. Here, the synthesis of a series of pyrimidine‐based 1,3,4‐oxadiazoles, in which the oxadiazole scaffold is attached to the pyrimidine ring via a methyleneoxy spacer, is described and their HDAC inhibitory activity studied. The target compounds were synthesized by sequence of reactions involving O‐alkylation of 2‐(methylthio)pyrimidin‐4(3H)‐ones with ethyl 2‐bromoethanoate followed by oxidation of the 2‐methylthio group, displacement of the obtained 2‐methylsulfonyl group with amines, hydrazinolysis of the obtained ethyl (2‐amino‐substituted pyrimidin‐4‐yloxy)acetates to give the corresponding hydrazides and their cyclization under the treatment with ethyl O‐ethyl xanthate or carbonyldiimidazole to 1,3,4‐oxadiazole‐2(3H)‐thiones and 1,3,4‐oxadiazol‐2(3H)‐one, correspondingly. In addition, two 1,3,4‐oxadiazole‐2(3H)‐thiones were converted into (N3)‐morpholinomethyl derivatives by the Mannich reaction with formaldehyde and morpholine. The yields of intermediates and target compounds ranged from moderate to excellent. The synthesized compounds were characterized by 1H and 13C NMR spectra and HRMS data, their purity was controlled by TLC. The synthesized pyrimidine‐based 1,3,4‐oxadiazoles (18 compounds) were tested as inhibitors of the HDAC4 and HDAC8 isoforms and their inhibitory activity was compared with that of Vorinostat. Most of the oxadiazolethiones containing methyl group at the position 6 of the pyrimidine moiety were found to be more selective towards HDAC8, while oxadiazolethiones with propyl group in the pyrimidine ring were active against HDAC4. Among the tested compounds, 5‐((2‐(dibutylamino)‐6‐propylpyrimidin‐4‐yloxy)methyl)‐1,3,4‐oxadiazole‐2(3H)‐thione (48) was found to have the strongest inhibitory activity for HDAC4 isoform (IC50 = 4.2 μM vs. IC50 = 59 μM for Vorinostat) while 5‐((2‐(cyclopentylamino)‐6‐propylpyrimidin‐4‐yloxy)methyl)‐1,3,4‐oxadiazole‐2(3H)‐thione (50) was the most potent HDAC8 inhibitor (IC50 = 6.8 μM).
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Disclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.