A series of allosteric kidney-type glutaminase (GLS) inhibitors possessing a mercaptoethyl (SCH₂CH₂) linker were synthesized in an effort to further expand the structural diversity of chemotypes derived from bis-2-(5-phenylacetamido-1,3,4-thiadiazol-2-yl)ethyl sulfide (BPTES), a prototype allosteric inhibitor of GLS. BPTES analog 3a with a mercaptoethyl linker between the two thiadiazole rings was found to potently inhibit GLS with an IC₅₀ value of 50 nM. Interestingly, the corresponding derivative with an n-propyl (CH₂CH₂CH₂) linker showed substantially lower inhibitory potency (IC₅₀ = 2.3 μM) while the derivative with a dimethylsulfide (CH₂SCH₂) linker showed no inhibitory activity at concentrations up to 100 μM, underscoring the critical role played by the mercaptoethyl linker in the high affinity binding to the allosteric site of GLS. Additional mercaptoethyl-linked compounds were synthesized and tested as GLS inhibitors to further explore SAR within this scaffold including derivatives possessing a pyridazine as a replacement for one of the two thiadiazole moiety.

合成了一系列具有巯基乙基 ( SCH ₂ CH ₂ ) 接头的变构肾型谷氨酰胺酶 (GLS) 抑制剂，以进一步扩展衍生自 bis-2-(5-phenylacetamido-1,3) 的化学型的结构多样性， 4-thiadiazol-2-yl)ethyl sulfide (BPTES)，一种 GLS 的原型变构抑制剂。发现在两个噻二唑环之间具有巯基乙基接头的BPTES 类似物3a可有效抑制 GLS，IC ₅₀值为 50 nM。有趣的是，具有正丙基 ( CH ₂ CH ₂ CH ₂ ) 接头的相应衍生物显示出显着较低的抑制效力 (IC ₅₀ = 2.3 μM），而具有二甲基硫醚 ( CH ₂ SCH ₂ ) 接头的衍生物在浓度高达 100 μM 时没有显示出抑制活性，这突出了巯乙基接头在与 GLS 变构位点的高亲和力结合中所起的关键作用。合成了额外的巯基乙基化合物并作为 GLS 抑制剂进行了测试，以进一步探索该支架内的 SAR，包括具有哒嗪作为两个噻二唑部分之一的替代物的衍生物。