Pomeislová, Alice, Otmar, Miroslav, Rubešová, Petra, Benýšek, Jakub, Matoušová, Marika, Mertlíková-Kaiserová, Helena, Pohl, Radek, Poštová Slavětínská, Lenka, Pomeisl, Karel, and Krečmerová, Marcela
• 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. 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. [ABSTRACT FROM AUTHOR]