Drug Discovery Chemistry Team, CSIRO, Clayton, VIC 3168, Australia.
State Key Laboratory of Respiratory Disease, Guangdong-Hong Kong-Macao Joint Laboratory of Respiratory Infectious Diseases, China-New Zealand Joint Laboratory on Biomedicine and Health, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, China; University of Chinese Academy of Sciences, Beijing, 100049, China.
Bioorg Med Chem Lett. 2023 Aug 15;92:129391. doi: 10.1016/j.bmcl.2023.129391. Epub 2023 Jun 25.
A series of 2-(tetrazol-5-yl)sulfonylacetamide derivatives were synthesized and evaluated for their in vitro inhibitory activity against Mycobacterium tuberculosis (Mtb) and Mycobacterium marinum (Mm). The most active compounds exhibited in vitro MIC values of 1.25 μg/mL against Mtb, but they were less effective against Mm (MIC ≥ 10 μg/mL). Despite the most active compounds having favourable physicochemical properties and one of them having a half-life of ∼3 h when incubated with mouse liver microsomes, two representative highly active compounds showed strong chemical reactivity to cysteine derivatives, as surrogate in vivo sulfur-centred nucleophiles, indicating excessive electrophilicity, and therefore, likely indiscriminate chemical reactivity in vivo, representing an unacceptably high risk of general toxicity, and low likelihood of being therapeutically effective.
一系列 2-（四唑-5-基）磺酰基乙酰胺衍生物被合成并评估了它们对结核分枝杆菌（Mtb）和海分枝杆菌（Mm）的体外抑制活性。最活跃的化合物对 Mtb 的体外 MIC 值为 1.25μg/mL，但对 Mm 的效果较差（MIC≥10μg/mL）。尽管最活跃的化合物具有有利的物理化学性质，其中一种化合物在与小鼠肝微粒体孵育时半衰期约为 3 小时，但两种代表性的高活性化合物对半胱氨酸衍生物表现出很强的化学反应性，作为体内含硫亲核试剂的替代物，表明其具有过高的亲电性，因此，很可能在体内具有不可区分的化学反应性，代表着极高的一般毒性风险和低的治疗效果可能性。
