Braun-Cornejo Maria, Platteschorre Mitchell, de Vries Vincent, Bravo Patricia, Sonawane Vidhisha, Hamed Mostafa M, Haupenthal Jörg, Reiling Norbert, Rottmann Matthias, Piet Dennis, Maas Peter, Diamanti Eleonora, Hirsch Anna K H
Specs Compound Handling, B.V., Bleiswijkseweg 55, Zoetermeer 2712 PB, The Netherlands.
Department of Pharmacy, Saarland University, Campus Building E8.1, Saarbrücken 66123, Germany.
JACS Au. 2025 Feb 21;5(3):1146-1156. doi: 10.1021/jacsau.4c00935. eCollection 2025 Mar 24.
In this study, we synthesized a library of eNTRy-rule-compliant compounds by introducing ionizable nitrogen atoms to an antimalarial compound. These positively charged derivatives gained activity against both Gram-negative and -positive bacteria, , and boosted inhibition to the double-digit nanomolar range. Overcoming and remaining inside the cell envelope of Gram-negative bacteria (GNB) is one of the major difficulties in antibacterial drug discovery and development. The eNTRy rules (N = ionizable nitrogen, T = low three-dimensionality, R = rigidity) can be a useful structural guideline to improve accumulation of small molecules in GNB. With the aim of unlocking Gram-negative activity, we added amines and (cyclic) -alkyl guanidines to an already flat and rigid pyrazole-amide class as a representative example for our investigation. To test their performance, we compared these eNTRy-rule-compliant compounds to closely related noncompliant ones through phenotypic screening of various pathogens (, , , , , , and ), obtaining a handful of broad-spectrum hits. The results support the working hypothesis and even extend its applicability. The studied pyrazole-amide class adheres to the eNTRy rules; noncompliant compounds do not kill any of the bacteria tested, while compliant compounds largely showed growth inhibition of Gram-negative, -positive, and bacteria in the single-digit micromolar range.
在本研究中，我们通过将可电离氮原子引入一种抗疟化合物，合成了一系列符合eNTRy规则的化合物。这些带正电荷的衍生物对革兰氏阴性菌和革兰氏阳性菌均具有活性，并将抑制作用提高到两位数的纳摩尔范围。克服并滞留在革兰氏阴性菌（GNB）的细胞包膜内是抗菌药物发现和开发中的主要困难之一。eNTRy规则（N = 可电离氮，T = 低三维性，R = 刚性）可作为提高小分子在GNB中积累的有用结构指导。为了开启革兰氏阴性菌活性，我们将胺类和（环状）烷基胍添加到一个已经扁平且刚性的吡唑酰胺类化合物中，作为我们研究的一个代表性例子。为了测试它们的性能，我们通过对各种病原体（、、、、、和）进行表型筛选，将这些符合eNTRy规则的化合物与密切相关的不符合规则的化合物进行比较，获得了一些广谱活性化合物。结果支持了工作假设，甚至扩展了其适用性。所研究的吡唑酰胺类化合物符合eNTRy规则；不符合规则的化合物对任何测试细菌均无杀灭作用，而符合规则的化合物在个位数微摩尔范围内对革兰氏阴性菌、革兰氏阳性菌和细菌大多表现出生长抑制作用。
