Pneumonia caused by bacterium S. pneumoniae is a severe acute respiratory infectious disease with high morbidity and mortality, especially for children and immunity-compromised patients. The emergence of multidrug-resistant S. pneumoniae also presents a challenge to human health. Leucyl-tRNA synthetase (LeuRS) catalyzes the attachment of L-leucine to tRNA^Leu, which plays an essential role in protein translation and is considered an attractive antimicrobial drug target. In the present work, benzhydrol-oxaborole hybrid compounds were designed and synthesized as inhibitors of S. pneumoniae LeuRS. Exploration of the phenyl ring near Lysine 389 eventually yielded compounds 46 and 54 with submicromolar inhibitory potency. The co-crystal of compound 54 in the editing domain pocket of SpLeuRS was obtained and confirmed the formation of an additional hydrogen bond between the carbonyl of 54 and Lysine 389. It also showed anti-pneumococcal activity in vitro. The structure-activity relationship was discussed. This work will provide an essential foundation for the further development of anti-pneumococcal agents by targeting LeuRS.

由肺炎链球菌引起的肺炎是一种严重的急性呼吸道传染病，发病率和死亡率都很高，尤其是儿童和免疫力低下的患者。耐多药肺炎链球菌的出现也对人类健康提出了挑战。亮氨酰-tRNA 合成酶 (LeuRS) 催化 L-亮氨酸与 tRNA ^{Leu 的连接}，其在蛋白质翻译中起重要作用，被认为是有吸引力的抗菌药物靶点。在目前的工作中，苯甲醇-氧杂硼杂化化合物被设计和合成为肺炎链球菌LeuRS 的抑制剂。对赖氨酸 389 附近苯环的探索最终得到了化合物46和54具有亚微摩尔抑制效力。在Sp LeuRS的编辑域口袋中获得了化合物54的共晶，并证实了在54的羰基和赖氨酸 389之间形成了额外的氢键。它还在体外显示出抗肺炎球菌活性。讨论了构效关系。这项工作将为通过靶向 LeuRS 进一步开发抗肺炎球菌药物提供必要的基础。