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 N⁵-protected phosphonic acids. The subsequent attempts to remove the protecting group from N⁵ 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 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.

类似于抗病毒非环状核苷膦酸酯，一系列5-氨基-3-氧代-1,2,4-噻二唑-3（2 ħ） -酮轴承2- phosphonomethoxyethyl（PME）或3-羟基-2-（已合成杂环部分 2 位的膦酰基甲氧基）丙基（HPMP）基团。PME-和HPMP-胺的二异丙酯已经转化为N-取代的脲，然后与苯甲酰基、乙氧基羰基和Fmoc异硫氰酸酯反应得到相应的硫代缩二脲，它们被氧化环化为5-氨基-3-氧代的二异丙酯-2-PME- 或 2-HPMP- 1,2,4-thiadiazol-3(2 H )-ones。膦酸酯基团用溴代三甲基硅烷裂解，产生N ⁵-受保护的膦酸。随后在碱性条件下从N ⁵去除保护基团的尝试导致 1,2,4-噻二唑环断裂。类似地，具有先前未保护的 5-氨基-1,2,4-噻二唑酮碱部分的化合物仅以膦酸酯的形式稳定。新制备的 1,2,4-噻二唑-3(2 H)-ones 被探索作为半胱氨酸依赖性酶的潜在抑制剂 - 人组织蛋白酶 K (CatK) 和糖原合酶激酶 3β (GSK-3β)。几种化合物在低微摩尔范围内对两种酶都表现出抑制活性。其中一些对 GSK-3β 的抑制效力与噻二唑 GSK-3β 抑制剂tideglusib 的抑制效力相似，而另一些则表现出更有利的毒性特征，同时保持良好的抑制活性。