Department of Pharmaceutical Organic Chemistry, College of Pharmacy, Al-Azhar University, Cairo 11884, Egypt.
Department of Comparative Pathobiology, Purdue University, College of Veterinary Medicine, West Lafayette, IN 47907, USA.
Eur J Med Chem. 2017 Apr 21;130:73-85. doi: 10.1016/j.ejmech.2017.02.044. Epub 2017 Feb 21.
A new class of diphenylurea was identified as a novel antibacterial scaffold with an antibacterial spectrum that includes highly resistant staphylococcal isolates, namely methicillin- and vancomycin-resistant Staphylococcus aureus (MRSA & VRSA). Starting with a lead compound 3 that carries an aminoguanidine functionality from one side and a n-butyl moiety on the other ring, several analogues were prepared. Considering the pharmacokinetic parameters as a key factor in structural optimization, the structure-activity-relationships (SARs) at the lipophilic side chain were rigorously examined leading to the discovery of the cycloheptyloxyl analogue 21n as a potential drug-candidate. This compound has several notable advantages over vancomycin and linezolid including rapid killing kinetics against MRSA and the ability to target and reduce the burden of MRSA harboring inside immune cells (macrophages). Furthermore, the potent anti-MRSA activity of 21n was confirmed in vivo using a Caenorhabditis elegans animal model. The present study provides a foundation for further development of diphenylurea compounds as potential therapeutic agents to address the burgeoning challenge of bacterial resistance to antibiotics.
一种新的二苯脲类化合物被鉴定为一种新型的抗菌支架，具有广谱的抗菌活性，包括高度耐药的葡萄球菌分离株，即耐甲氧西林和万古霉素的金黄色葡萄球菌（MRSA 和 VRSA）。以具有氨基胍功能的先导化合物 3 为起始点，在另一个环上带有正丁基部分，合成了几种类似物。考虑到药代动力学参数是结构优化的关键因素，对亲脂性侧链的构效关系（SARs）进行了严格的研究，发现环己基氧基类似物 21n 是一种有潜力的候选药物。与万古霉素和利奈唑胺相比，该化合物具有几个显著的优点，包括对 MRSA 的快速杀伤动力学以及靶向和减少携带免疫细胞（巨噬细胞）内的 MRSA 负担的能力。此外，在使用秀丽隐杆线虫动物模型的体内实验中，证实了 21n 对 MRSA 的强大活性。本研究为进一步开发二苯脲类化合物作为潜在的治疗剂提供了基础，以应对抗生素耐药性日益严重的挑战。
