Markuliak Mário, Kos Dominika, Vojáčková Veronika, Horváth Branislav, Švajdlenka Emil, Leskovská Janka, Pisárčik Martin, Kryštof Vladimír, Čížek Alois, Jampílek Josef, Lukáč Miloš
Department of Chemical Theory of Drugs, Faculty of Pharmacy, Comenius University Bratislava, Kalinčiakova 8, 832 32 Bratislava, Slovakia.
Department of Molecular Pharmacy, Faculty of Pharmacy, Masaryk University, Palackeho 1946/1, 612 00 Brno, Czech Republic.
Eur J Pharm Sci. 2025 Jun 11;212:107167. doi: 10.1016/j.ejps.2025.107167.
Bacterial resistance to antibiotics in use represents a critical threat to public health. The treatment of nosocomial, often life-threatening infections is often challenging and requires the search for new antibacterial compounds. In this study a series of phosphonium salts derived from bis(bibenzyl) isoperrottetin A were studied. Bis(bibenzyls) are compounds unique for liverworts. Phosphonium salts were prepared by an eight-step synthesis. The key steps in its preparation were the Ullmann reaction and the Wittig reaction. Ten phosphonium salts were prepared. Isoperrottetin A and its phosphonium salts were tested for antibacterial activity. Some of the compounds exhibit significant biological activity. Most of the prepared derivatives are more potent than the original isoperrottetin A. Compounds were evaluated for the antibacterial activity against selected Gram-positive bacteria such as Staphylococcus aureus, methicillin sensitive and resistant, Enterococcus faecalis and vancomycin sensitive and resistant and Gram-negative bacteria such as Escherichia coli, Pseudomonas aeruginosa, and Klebsiella pneumoniae. Mycobacterium smegmatis and Mycobacterium marinum belonging to the genus Mycobacterium were also tested. Besides antibacterial activity, the compounds inhibit cell breathing and show cytotoxic activity against melanoma cells, retinal and epithelial cells. The results of antibacterial tests showed that the most effective compound is 5,5',5'',5'''-[1,7(1),4,5(1,3)-tetrabenzenaoctaphane-1,4,5,8-tetrayltetrakis(oxy)]tetrakis(5-oxo-P,P,P-triphenylpentane-1-phosphonium) tetrabromide (4P). The values of minimum bactericidal concentration (MBC) against S. aureus methicillin sensitive and resistant and E. faecalis vancomycin sensitive and resistant were < 1 µM. At the same time, the compound does not involve damaging the cell wall, as is known for cationic amphiphilic compounds, and showed favorable safety profiles at MBC values. These findings highlight the potential of compounds found in liverworts as active agents against sensitive and resistant bacterial strains. Chemical modification of bis(bibenzyls) with a phosphonium cation is promising in preparation of potent microbicidal compounds.
细菌对现有抗生素产生耐药性对公众健康构成了严重威胁。医院内感染往往危及生命，其治疗通常具有挑战性，需要寻找新的抗菌化合物。在本研究中，对一系列源自双（联苄基）异珀洛苔色素A的鏻盐进行了研究。双（联苄基）是苔类植物特有的化合物。鏻盐通过八步合成法制备。其制备的关键步骤是乌尔曼反应和维蒂希反应。制备了十种鏻盐。对异珀洛苔色素A及其鏻盐进行了抗菌活性测试。一些化合物表现出显著的生物活性。大多数制备的衍生物比原始的异珀洛苔色素A更有效。对这些化合物针对选定的革兰氏阳性菌如金黄色葡萄球菌（包括甲氧西林敏感和耐药菌株）、粪肠球菌（包括万古霉素敏感和耐药菌株）以及革兰氏阴性菌如大肠杆菌、铜绿假单胞菌和肺炎克雷伯菌的抗菌活性进行了评估。还测试了属于分枝杆菌属的耻垢分枝杆菌和海分枝杆菌。除抗菌活性外，这些化合物还抑制细胞呼吸，并对黑色素瘤细胞、视网膜细胞和上皮细胞表现出细胞毒性活性。抗菌测试结果表明，最有效的化合物是5,5',5'',5'''-[1,7(1),4,5(1,3)-四苯并辛八烷-1,4,5,8-四氧代]四（5-氧代-P,P,P-三苯基戊烷-1-鏻）四溴化物（4P）。其对甲氧西林敏感和耐药的金黄色葡萄球菌以及万古霉素敏感和耐药的粪肠球菌的最低杀菌浓度（MBC）值<1μM。同时，该化合物不像阳离子两亲性化合物那样会破坏细胞壁，并且在MBC值时显示出良好的安全性。这些发现突出了苔类植物中发现的化合物作为针对敏感和耐药细菌菌株的活性剂的潜力。用鏻阳离子对双（联苄基）进行化学修饰在制备强效杀菌化合物方面很有前景。
