New antibacterial compounds are urgently needed, especially for infections caused by the top-priority Gram-negative bacteria that are increasingly difficult to treat. Lipid A is a key component of the Gram-negative outer membrane and the LpxH enzyme plays an important role in its biosynthesis, making it a promising antibacterial target. Inspired by previously reported -methyl-sulfonamidobenzamide-based LpxH inhibitors, novel benzamide substitutions were explored in this work to assess their activity. Our findings reveal that maintaining wild-type antibacterial activity necessitates removal of the -methyl group when shifting the -methyl-sulfonamide to the meta-position. This discovery led to the synthesis of -sulfonamidobenzamide analogs with potent antibacterial activity and enzyme inhibition. Moreover, we demonstrate that modifying the benzamide scaffold can alter blocking of the cardiac voltage-gated potassium ion channel hERG. Furthermore, two LpxH-bound X-ray structures show how the enzyme-ligand interactions of the -sulfonamidobenzamide analogs differ from those of the previously reported analogs. Overall, our study has identified -sulfonamidobenzamide derivatives as promising LpxH inhibitors with the potential for optimization in future antibacterial hit-to-lead programs.

中文翻译：

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基于间磺酰胺苯甲酰胺的抗菌 LpxH 抑制剂的设计、合成和体外生物学评价


迫切需要新的抗菌化合物，特别是对于越来越难以治疗的首要革兰氏阴性菌引起的感染。脂质 A 是革兰氏阴性外膜的关键成分，LpxH 酶在其生物合成中发挥着重要作用，使其成为一个有前景的抗菌靶点。受先前报道的基于 β-磺酰胺基苯甲酰胺的 LpxH 抑制剂的启发，本工作探索了新型苯甲酰胺取代物以评估其活性。我们的研究结果表明，维持野生型抗菌活性需要在将-甲基-磺酰胺转移到间位时去除-甲基。这一发现导致了具有有效抗菌活性和酶抑制作用的β-磺酰胺苯甲酰胺类似物的合成。此外，我们证明修饰苯甲酰胺支架可以改变心脏电压门控钾离子通道 hERG 的阻断。此外，两个LpxH结合的X射线结构显示了磺酰胺基苯甲酰胺类似物的酶-配体相互作用与先前报道的类似物的酶-配体相互作用有何不同。总体而言，我们的研究已确定 β-磺酰胺苯甲酰胺衍生物是有前途的 LpxH 抑制剂，具有在未来抗菌先导项目中优化的潜力。