Department of Pharmaceutical Organic Chemistry, College of Pharmacy, Al-Azhar University, 1-Elmokhayem Eldaem Street, Cairo 11884, Egypt.
Department of Comparative Pathobiology, College of Veterinary Medicine, Purdue University, 725 Harrison Street, West Lafayette, Indiana 47907, United States.
ACS Infect Dis. 2020 Nov 13;6(11):2887-2900. doi: 10.1021/acsinfecdis.0c00137. Epub 2020 Oct 8.
Exploring the structure-activity relationship (SAR) at the cationic part of arylthiazole antibiotics revealed hydrazine as an active moiety. The main objective of the study is to overcome the inherited toxicity associated with the free hydrazine. A series of hydrocarbon bridges was inserted in between the groups, to separate the two amino groups. Hence, the aminomethylpiperidine-containing analog was identified as a new promising antibacterial agent with efficient antibacterial and pharmacokinetic profiles. Briefly, compound outperformed vancomycin in terms of the antibacterial spectrum against vancomycin-resistant staphylococcal and enterococcal strains with minimum inhibitory concentrations (MICs) ranging from 2 to 4 μg/mL, which is a faster bactericidal mode of action, completely eradicating the high staphylococcal burden within 6-8 h, and it has a unique ability to completely clear intracellular staphylococci. In addition, the initial pharmacokinetic assessment confirmed the high metabolic stability of compound (biological half-life >4 h); it had a good extravascular distribution and maintained a plasma concentration higher than the average MIC value for over 12 h. Moreover, compound significantly reduced MRSA burden in an MRSA skin infection mouse experiment. These attributes collectively suggest that compound is a good therapeutic candidate for invasive staphylococcal and enterococcal infections. From a mechanistic point of view, compound inhibited undecaprenyl diphosphate phosphatase (UppP) with an IC value of 29 μM.
探索芳基噻唑类抗生素阳离子部分的构效关系（SAR）表明，肼是一种活性部分。本研究的主要目的是克服与游离肼相关的遗传毒性。在两个氨基之间插入一系列碳氢桥，以将两个氨基分开。因此，含有氨甲基哌啶的类似物 被鉴定为一种新的有前途的抗菌剂，具有有效的抗菌和药代动力学特性。简而言之，化合物 在抗菌谱方面优于万古霉素，对万古霉素耐药的葡萄球菌和肠球菌菌株的最低抑菌浓度（MIC）范围为 2 至 4 μg/mL，具有更快的杀菌作用，可在 6-8 小时内完全消除高负荷的金黄色葡萄球菌，并且具有独特的能力可完全清除细胞内的金黄色葡萄球菌。此外，初步药代动力学评估证实化合物 的代谢稳定性很高（生物半衰期>4 小时）；它具有良好的血管外分布，并在超过 12 小时的时间内使血浆浓度保持在高于平均 MIC 值的水平。此外，化合物 在 MRSA 皮肤感染小鼠实验中显著降低了 MRSA 的负担。这些特性表明，化合物 是治疗侵袭性葡萄球菌和肠球菌感染的良好候选药物。从机制的角度来看，化合物 以 29 μM 的 IC 值抑制了十一烯基二磷酸磷酸酶（UppP）。
