1, 2, 4-Thiadiazole acyclic nucleoside phosphonates as inhibitors of cysteine dependent enzymes cathepsin K and GSK-3β. (15th February 2021)

• Record Type: Journal Article
• Authors: Pomeislová, Alice; Otmar, Miroslav; Rubešová, Petra; Benýšek, Jakub; Matoušová, Marika; Mertlíková-Kaiserová, Helena; Pohl, Radek; Poštová Slavětínská, Lenka; Pomeisl, Karel; Krečmerová, Marcela
• Is Part Of: Bioorganic & medicinal chemistry. Volume 32(2021)
• Publication Date: 2021-02-15
• Subjects: Thiadiazoles -- 5-Amino-1, 2, 4-thiadiazol-3-(2H)-one -- Acyclic nucleoside phosphonates -- Epigenetic -- Cathepsin K, Glycogen synthase kinase 3β; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; Biochemistry -- Periodicals; Chemistry, Clinical -- Periodicals; Chemistry, Organic -- Periodicals; Chimie bio-organique -- Périodiques; Chimie pharmaceutique -- Périodiques; 615.19
• DOI: 10.1016/j.bmc.2021.115998
• Languages: English
• ISSNs: 0968-0896

Abstract

Graphical abstract: Highlights: New acyclic nucleotide analogs with 1, 2, 4-thiadiazole base were synthesized. 5-Amino-1, 2, 4-thiadiazol-3(2 H )-one derivatives inhibit Cathepsin K and GSK-3β. 1, 2, 4-Thiadiazol-3(2 H )-one ring is stabilized by substitution at the 5-amino group. Abstract: In analogy to antiviral acyclic nucleoside phosphonates, a series of 5-amino-3-oxo-1, 2, 4-thiadiazol-3(2 H )-ones bearing a 2-phosphonomethoxyethyl (PME) or 3-hydroxy-2-(phosphonomethoxy)propyl (HPMP) group at the position 2 of the heterocyclic moiety has been synthesized. Diisopropyl esters of PME- and HPMP-amines have been converted to the N -substituted ureas and then reacted with benzoyl, ethoxycarbonyl, and Fmoc isothiocyanates to give the corresponding thiobiurets, which were oxidatively cyclized to diisopropyl esters of 5-amino-3-oxo-2-PME- or 2-HPMP- 1, 2, 4-thiadiazol-3(2 H )-ones. The phosphonate ester groups were cleaved with bromotrimethylsilane, yielding N 5 -protected phosphonic acids. The subsequent attempts to remove the protecting group from N 5 under alkaline conditions resulted in the cleavage of the 1, 2, 4-thiadiazole ring. Similarly, compounds with a previously unprotected 5-amino-1, 2, 4-thiadiazolone base moiety were stable only in the form of phosphonate esters. The series of twenty-one newly prepared 1, 2, 4-thiadiazol-3(2 H )-ones were explored as potential inhibitors of cysteine-dependent enzymes – human cathepsin K (CatK) and glycogen synthase kinase 3β (GSK-3β). Several compounds exhibited an inhibitory activity toward both enzymes in the low micromolar range. The inhibitory potency of some of them toward GSK-3β was similar to that of the thiadiazole GSK-3β inhibitor tideglusib, whereas others exhibited more favorable toxicity profile while retaining good inhibitory activity.