Gonzalez Lopez Edwin J, Martínez Sol R, Aiassa Virginia, Santamarina Sofía C, Domínguez Rodrigo E, Durantini Edgardo N, Heredia Daniel A
IDAS-CONCIET-UNRC, Departamento de Química, Facultad de Ciencias Exactas Físico-Químicas y Naturales, Universidad Nacional de Río Cuarto, Agencia Postal Nro. 3, Río Cuarto X5804BYA, Argentina.
IITEMA-CONICET, Departamento de Química, Facultad de Ciencias Exactas Físico-Químicas y Naturales, Universidad Nacional de Río Cuarto, Agencia Postal Nro. 3, Río Cuarto X5804BYA, Argentina.
Pharmaceutics. 2023 Jan 24;15(2):392. doi: 10.3390/pharmaceutics15020392.
The increase in the antibiotic resistance of bacteria is a serious threat to public health. Photodynamic inactivation (PDI) of micro-organisms is a reliable antimicrobial therapy to treat a broad spectrum of complex infections. The development of new photosensitizers with suitable properties is a key factor to consider in the optimization of this therapy. In this sense, four corroles were designed to study how the number of cationic centers can influence the efficacy of antibacterial photodynamic treatments. First, 5,10,15-Tris(pentafluorophenyl)corrole () and 5,15-bis(pentafluorophenyl)-10-(4-(trifluoromethyl)phenyl)corrole () were synthesized, and then derivatized by nucleophilic aromatic substitution with 2-dimethylaminoethanol and 2-(dimethylamino)ethylamine, obtaining corroles and , respectively. The straightforward synthetic strategy gave rise to macrocycles with different numbers of tertiary amines that can acquire positive charges in an aqueous medium by protonation at physiological pH. Spectroscopic and photodynamic studies demonstrated that their properties as chromophores and photosensitizers were unaffected, regardless of the substituent groups on the periphery. All tetrapyrrolic macrocycles were able to produce reactive oxygen species (ROS) by both photodynamic mechanisms. Uptake experiments, the level of ROS produced in vitro, and PDI treatments mediated by these compounds were assessed against clinical strains: methicillin-resistant and . In vitro experiments indicated that the peripheral substitution significantly affected the uptake of the photosensitizers by microbes and, consequently, the photoinactivation performance. was the most effective in killing both Gram-positive and Gram-negative bacteria (inactivation > 99.99%). This work lays the foundations for the development of new corrole derivatives having pH-activable cationic groups and with plausible applications as effective broad-spectrum antimicrobial photosensitizers.
细菌对抗生素耐药性的增加对公众健康构成严重威胁。微生物的光动力灭活（PDI）是一种可靠的抗菌疗法，可用于治疗多种复杂感染。开发具有合适特性的新型光敏剂是优化该疗法时需要考虑的关键因素。从这个意义上讲，设计了四种卟吩来研究阳离子中心的数量如何影响抗菌光动力治疗的效果。首先，合成了5,10,15-三（五氟苯基）卟吩（）和5,15-双（五氟苯基）-10-（4-（三氟甲基）苯基）卟吩（），然后分别用2-二甲基氨基乙醇和2-（二甲基氨基）乙胺通过亲核芳香取代进行衍生化，分别得到卟吩 和 。这种直接的合成策略产生了具有不同叔胺数量的大环化合物，这些叔胺在生理pH值下通过质子化可在水性介质中获得正电荷。光谱和光动力研究表明，无论外围的取代基如何，它们作为发色团和光敏剂的性质均未受影响。所有四吡咯大环化合物都能够通过两种光动力机制产生活性氧（ROS）。针对临床菌株：耐甲氧西林的 和 ，评估了摄取实验、体外产生的ROS水平以及由这些化合物介导的PDI治疗。体外实验表明，外围取代显著影响微生物对光敏剂的摄取，进而影响光灭活性能。 在杀死革兰氏阳性菌和革兰氏阴性菌方面最有效（灭活率> 99.99%）。这项工作为开发具有pH可激活阳离子基团且有望作为有效的广谱抗菌光敏剂的新型卟吩衍生物奠定了基础。
