Izmest'ev Evgeniy S, Pestova Svetlana V, Kolesnikova Alena I, Baidamshina Diana R, Kayumov Airat R, Rubtsova Svetlana A
Institute of Chemistry, FRC Komi Science Center Ural Branch of the Russian Academy of Sciences, 48, Pervomaiskaya St., 167000, Syktyvkar, Russian Federation.
Institute of Fundamental Medicine and Biology, Kazan Federal University, 18, Kremlevskaya St., 420008, Kazan, Russian Federation.
ChemMedChem. 2023 Dec 14;18(24):e202300358. doi: 10.1002/cmdc.202300358. Epub 2023 Nov 10.
This study was the first to synthesize terpene-containing conjugates of fluoroquinolones, ciprofloxacin and norfloxacin, and to evaluate their antibacterial activity against gram-positive methicillin sensitive (MSSA) and methicillin resistant (MRSA) S. aureus, gram-negative P. aeruginosa as well as antifungal activity against C. albicans. The ability of obtained fluoroquinolones to inhibit S. aureus growth was found to depend upon the presence of a linker separating the bulky terpene and fluoroquinolone fragments, and this activity diminished with increasing its length. The highest activity against MSSA was demonstrated by ciprofloxacin derivatives with campholenic (MIC 1 μg/mL) and 2-(isobornan-2-yl-sulfanyl)acetyl (MIC 0.5 μg/mL) substituents. The compound with the last fragment showed high activity against MRSA (MIC 8 μg/mL). The terpene-functionalized norfloxacin derivatives generally proved to be less active than those containing ciprofloxacin fragment. Camphor-10-sulfonylamide derivative with the ciprofloxacin fragment was the only one of all compounds that showed high antifungal activity against C. albicans (8 μg/mL). The study presents data on docking fluoroquinolones to S. aureus DNA gyrase to explain the reasons for manifestation or disappearance of antibacterial activity. The cytotoxicity of fluoroquinolones that showed any antimicrobial activity was investigated against bovine primary lung cells, and they were found to be not toxic in most cases.
本研究首次合成了含萜类的氟喹诺酮类共轭物、环丙沙星和诺氟沙星，并评估了它们对革兰氏阳性甲氧西林敏感（MSSA）和甲氧西林耐药（MRSA）金黄色葡萄球菌、革兰氏阴性铜绿假单胞菌的抗菌活性以及对白色念珠菌的抗真菌活性。研究发现，所获得的氟喹诺酮类抑制金黄色葡萄球菌生长的能力取决于连接庞大萜类和氟喹诺酮片段的连接子的存在，且随着连接子长度增加，这种活性会降低。具有莰烯基（MIC 1 μg/mL）和2-（异冰片-2-基硫烷基）乙酰基（MIC 0.5 μg/mL）取代基的环丙沙星衍生物对MSSA表现出最高活性。具有后一种片段的化合物对MRSA表现出高活性（MIC 8 μg/mL）。一般来说，萜类功能化的诺氟沙星衍生物比含环丙沙星片段的衍生物活性更低。含环丙沙星片段的樟脑-10-磺酰胺衍生物是所有化合物中唯一对白色念珠菌表现出高抗真菌活性（8 μg/mL）的。该研究展示了氟喹诺酮类与金黄色葡萄球菌DNA促旋酶对接的数据，以解释抗菌活性表现或消失的原因。对表现出任何抗菌活性的氟喹诺酮类对牛原代肺细胞的细胞毒性进行了研究，发现大多数情况下它们无毒。
