1,2,4-Thiadiazole acyclic nucleoside phosphonates as inhibitors of cysteine dependent enzymes cathepsin K and GSK-3β

In analogy to antiviral acyclic nucleoside phosphonates, a series of 5-amino-3-oxo-1,2,4-thiadiazol-3(2H)-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(2H)-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(2H)-ones were explored as potential inhibitors of cysteine-dependent enzymes - human cathepsin K (CatK) and glycogen synthase kinase 3 beta (GSK-3 beta. Several compounds exhibited an inhibitory activity toward both enzymes in the low micromolar range. The inhibitory potency of some of them toward GSK-3 beta was similar to that of the thiadiazole GSK-3 beta inhibitor tideglusib, whereas others exhibited more favorable toxicity profile while retaining good inhibitory activity.

Automated summary

A series of novel 1,2,4-thiadiazol-3(2H)-ones were synthesized and explored as potential inhibitors of cysteine-dependent enzymes - human cathepsin K and glycogen synthase kinase 3 beta. Some compounds exhibited inhibitory activity toward both enzymes in the low micromolar range, with some showing similar inhibitory potency to tideglusib towards GSK-3 beta but with more favorable toxicity profile.