We describe the synthesis, characterization, and in vitro antibacterial evaluation of a library of novel compounds based on 1,2,3‐triazolo phosphonate framework along with the evaluation of DNA gyrase inhibitory potential of a promising molecule in silico. Preparation of these compounds was carried out via a multistep sequence comprising of the Abramov reaction followed by the Cu(I)‐catalyzed azide–alkyne cycloaddition (CuAAC) as the key steps. Various α‐hydroxyphosphonate derivatives containing either a secondary or tertiary alcohol at the α position were prepared. When screened for their antibacterial activities in vitro using a Gram‐positive (Staphylococcus aureus) and three Gram‐negative (Escherichia coli, Klebsiella pneumoniae and Pseudomonas aeruginosa) strains, majority of these derivatives exhibited reasonable to good effects with the analogue 5k being active against all the strains. The SAR analysis indicated that the activity was influenced by the position of the α‐hydroxyphosphonate moiety as well as the substituent present on the benzene ring attached to the 1,2,3‐triazole ring. Moreover, the compound 5k showed strong interactions with the DNA active site when docked into the DNA gyrase in silico. Thus, the 1,2,3‐triazolo phosphonate derivative 5k appeared to be a novel and promising hit molecule that deserves further study as a potential antibacterial agent.

中文翻译：

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新型1,2,3-三唑并膦酸酯衍生物作为潜在的抗菌剂

我们描述了基于1,2,3-三唑并膦酸酯骨架的新型化合物文库的合成，表征和体外抗菌评估，以及对有希望的分子在计算机模拟中对DNA促旋酶抑制潜力的评估。这些化合物的制备是通过一个多步骤序列进行的，其中包括Abramov反应，然后是Cu（I）催化的叠氮化物-炔烃环加成（CuAAC）作为关键步骤。制备了各种在α位置含有仲或叔醇的α-羟基膦酸酯衍生物。当使用革兰氏阳性菌（金黄色葡萄球菌）和三种革兰氏阴性菌（大肠杆菌，肺炎克雷伯菌和这些铜绿假单胞菌菌株中，大多数衍生物表现出合理至良好的效果，而类似物5k对所有菌株均具有活性。SAR分析表明，该活性受α-羟基膦酸酯部分的位置以及与1,2,3-三唑环相连的苯环上存在的取代基的影响。此外，化合物5k在计算机中对接至DNA促旋酶时显示出与DNA活性位点的强相互作用。因此，1,2,3-三唑并膦酸酯衍生物5k似乎是一种新颖而有希望的命中分子，作为潜在的抗菌剂值得进一步研究。