State-Key Laboratory and Research Institute of Elemento-Organic Chemistry, National Pesticide Engineering Research Center (Tianjin), College of Chemistry, Nankai University, Tianjin, 300071, China.
State Key Laboratory of Medicinal Chemical Biology, Nankai University, Tianjin, 300071, China; Tianjin International Joint Academy of Biotechnology and Medicine, Tianjin, 300457, China.
Eur J Med Chem. 2019 Apr 1;167:472-484. doi: 10.1016/j.ejmech.2019.02.002. Epub 2019 Feb 14.
Since pyrithiobac (PTB) is a successful commercial herbicide with very low toxicity against mammals, it is worth exploring its derivatives for an extensive study. Herein, a total of 35 novel compounds were chemically synthesized and single crystal of 6-6 was obtained to confirm the molecular structure of this family of compounds. The novel PTB derivatives were fully evaluated against various biological platforms. From the bioassay results, the best AHAS inhibitor 6-22 displayed weaker herbicidal activity but stronger anti-Candida activity than PTB did. For plant pathogenic fungi, 6-26 showed excellent activity at 50 mg/L dosage. Preliminary insecticidal activity and antiviral activity were also observed for some title compounds. Strikingly, 6-5 exhibited a promising inhibitory activity against SARS-CoV M with IC of 4.471 μM and a low cellular cytotoxicity against mammalian 293 T cells. Based on the results of molecular modeling, HOMO-1 was considered to be a factor that affects AHAS inhibition and a possible binding mode of 6-5 with SARS-CoV M was predicted. This is the first time that PTB derivatives have been studied as biological agents other than herbicides. The present research hence has suggested that more attentions should be paid to compounds belonging to this family to develop novel agrochemicals or medicines.
由于吡噻菌胺（PTB）是一种毒性非常低的成功的商业除草剂，因此值得探索其衍生物以进行广泛的研究。在此，共合成了 35 种新型化合物，并获得了 6-6 的单晶以确定该类化合物的分子结构。对新型 PTB 衍生物进行了全面的生物活性评价。从生物测定结果来看，AHAS 抑制剂 6-22 显示出比 PTB 更弱的除草活性，但更强的抗假丝酵母活性。对于植物病原真菌，6-26 在 50mg/L 剂量下表现出优异的活性。一些标题化合物也表现出初步的杀虫活性和抗病毒活性。值得注意的是，6-5 对 SARS-CoV M 表现出有希望的抑制活性，IC 为 4.471µM，对哺乳动物 293T 细胞的细胞毒性较低。基于分子建模的结果，认为 HOMO-1 是影响 AHAS 抑制的一个因素，并预测了 6-5 与 SARS-CoV M 的可能结合模式。这是首次将 PTB 衍生物作为除除草剂以外的生物制剂进行研究。因此，本研究建议应更多地关注属于该家族的化合物，以开发新型农药或药物。
