Ashraf Kerolos, Yasrebi Kaveh, Adeniyi Emmanuel Tola, Hertlein Tobias, Ohlsen Knut, Lalk Michael, Erdmann Frank, Hilgeroth Andreas
Institute of Pharmacy, Martin Luther University Halle-Wittenberg, Halle, Germany,
Institute of Molecular Infection Biology, Julius Maximilians University Würzburg, Würzburg, Germany.
Drug Des Devel Ther. 2019 Jan 10;13:275-283. doi: 10.2147/DDDT.S184965. eCollection 2019.
Resistance developments against established antibiotics are an emerging problem for antibacterial therapies. Infections with and methicillin-resistant (MRSA) have become more difficult to treat with standard antibiotics that often fail, especially against MRSA. In consequence, novel antibiotics are urgently needed. Antibiotics from natural sources own complicated structures that cause difficulties for a chemical synthetic production. We developed novel small-molecule antibacterials that are easily accessible in a simple one-pot synthesis. The central indolonaphthalene core is substituted with indole residues at various positions. Both the varied indole substitutions and their positions at the molecular scaffold influence the determined antibacterial activity against the evaluated strains. Best activities have been found for 5-chloro, -cyano, and -hydroxyl indole substitutions. Therefore, first promising lead compounds could be identified that are nontoxic in human HEK and SH-SY5Y cells and exceed the activity of used standard antibiotics, especially against MRSA.
对现有抗生素产生耐药性是抗菌治疗中一个新出现的问题。感染耐甲氧西林金黄色葡萄球菌（MRSA）后，使用标准抗生素治疗变得更加困难，这些抗生素常常失效，尤其是对MRSA。因此，迫切需要新型抗生素。天然来源的抗生素结构复杂，化学合成生产困难。我们开发了新型小分子抗菌剂，可通过简单的一锅法合成轻松获得。中心吲哚并萘核心在不同位置被吲哚残基取代。吲哚取代的多样性及其在分子支架上的位置都会影响对所评估菌株的抗菌活性。已发现5-氯、-氰基和-羟基吲哚取代具有最佳活性。因此，可以鉴定出首批有前景的先导化合物，它们在人HEK和SH-SY5Y细胞中无毒，且活性超过所用标准抗生素，尤其是对MRSA的活性。
