52057-90-6Relevant articles and documents
N-thiadiazole-4-hydroxy-2-quinolone-3-carboxamides bearing heteroaromatic rings as novel antibacterial agents: Design, synthesis, biological evaluation and target identification
Xue, Wenjie,Li, Xueyao,Ma, Guixing,Zhang, Hongmin,Chen, Ya,Kirchmair, Johannes,Xia, Jie,Wu, Song
, (2020/02/04)
Due to the occurrence of antibiotic resistance, bacterial infectious diseases have become a serious threat to public health. To overcome antibiotic resistance, novel antibiotics are urgently needed. N-thiadiazole-4-hydroxy-2-quinolone-3-carboxamides are a potential new class of antibacterial agents, as one of its derivatives was identified as an antibacterial agent against S. aureus. However, no potency-directed structural optimization has been performed. In this study, we designed and synthesized 37 derivatives, and evaluated their antibacterial activity against S. aureus ATCC29213, which led to the identification of ten potent antibacterial agents with minimum inhibitory concentration (MIC) values below 1 μg/mL. Next, we performed bacterial growth inhibition assays against a panel of drug-resistant clinical isolates, including methicillin-resistant S. aureus, and cytotoxicity assays with HepG2 and HUVEC cells. One of the tested compounds named 1-ethyl-4-hydroxy-2-oxo-N-(5-(thiazol-2-yl)-1,3,4-thiadiazol-2-yl)-1,2-dihydroquinoline-3-carboxamide (g37) showed 2 to 128-times improvement compared with vancomycin in term of antibacterial potency against the tested strains (MICs: 0.25–1 μg/mL vs. 1–64 μg/mL) and an optimal selective toxicity (HepG2/MRSA, 110.6 to 221.2; HUVEC/MRSA, 77.6–155.2). Further, comprehensive evaluation indicated that g37 did not induce resistance development of MRSA over 20 passages, and it has been confirmed as a bactericidal, metabolically stable, orally active antibacterial agent. More importantly, we have identified the S. aureus DNA gyrase B as its potential target and proposed a potential binding mode by molecular docking. Taken together, the present work reports the most potent derivative of this chemical series (g37) and uncovers its potential target, which lays a solid foundation for further lead optimization facilitated by the structure-based drug design technique.
Preparation of 2-amino-5-alkyl -1, 3, 4-thiadiazole
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Paragraph 0024-0026; 0052-0054, (2017/04/19)
The invention discloses a method for preparing 2-amino-5-alkyl-1,3,4-thiadiazole. The method comprises the following steps of adding A mol of thiosemicarbazide, B mol of carboxylic acid, C mol of phosphorus oxychloride and D mol of silica gel in a dry reaction container, grinding at a room temperature until the raw materials are completely reacted, and standing to obtain a crude product, wherein A: B: C = 1: (1 to 1.2): (1 to 1.2), and A: D = 1: (5 to 10); then adding alkaline solution in the crude product until the pH value of the obtained mixed solution is 8-8.2, then carrying out suction filtration on the mixed solution, dissolving the filter cake by a solvent and then further carrying out suction filtration, removing silica gel, then carrying out reduced pressure concentration on the finally-obtained filtrate, and removing the solvent to obtain 2-amino-5-alkyl-1,3,4-thiadiazole. The method disclosed by the invention is a solid-phase reaction, silica gel is used as a carrier, the operation process is simple, the reaction time is short, the reaction conditions are moderate, the equipment requirements are low, and the yield of the target product is up to more than 91%.
