A series of 108 novel quaternary bis-ammonium pyridoxine derivatives carrying various substituents at the quaternary nitrogen’s and acetal carbon was synthesized. Thirteen compounds exhibited antibacterial and antifungal activity (minimum inhibitory concentration (MIC) 0.25–16 µg/mL) comparable or superior than miramistin, benzalkonium chloride, and chlorhexidine. A strong correlation between the lipophilicity and antibacterial activity was found. The most active compounds had logP values in the range of 1–3, while compounds with logP > 6 and logP < 0 were almost inactive. All active compounds demonstrated cytotoxicity comparable with miramistin and chlorhexidine on HEK-293 cells and were three-fold less toxic when compared to benzalkonium chloride. The antibacterial activity of leading compound 5c12 on biofilm-embedded Staphylococcus aureus, Staphylococcus epidermidis, Escherichia coli or Pseudomonas aeruginosa was comparable or even higher than that of the benzalkonium chloride. In vivo 5c12 was considerably less toxic (LD50 1705 mg/kg) than benzalkonium chloride, miramistine, and chlorhexidine at oral administration on CD-1 mice. An aqueous solution of 5c12 (0.2%) was shown to be comparable to reference drugs efficiency on the rat’s skin model. The molecular target of 5c12 seems to be a cellular membrane as other quaternary ammonium salts. The obtained results make the described quaternary bis-ammonium pyridoxine derivatives promising and lead molecules in the development of the new antiseptics with a broad spectrum of antimicrobial activity.

中文翻译：

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新型吡哆醇双铵盐：合成和抗菌特性

合成了一系列 108 种在季氮和缩醛碳上带有各种取代基的新型季铵吡哆醇衍生物。13 种化合物表现出的抗菌和抗真菌活性（最低抑菌浓度 (MIC) 0.25–16 µg/mL）与米拉米斯汀、苯扎氯铵和氯己定相当或更好。发现亲脂性和抗菌活性之间有很强的相关性。最活跃的化合物的 logP 值在 1-3 的范围内，而 logP > 6 和 logP < 0 的化合物几乎没有活性。所有活性化合物对 HEK-293 细胞的细胞毒性与 Miramistin 和氯己定相当，并且与苯扎氯铵相比毒性低三倍。先导化合物5c12对生物膜包埋的金黄色葡萄球菌的抗菌活性，表皮葡萄球菌、大肠杆菌或铜绿假单胞菌与苯扎氯铵相当甚至更高。与苯扎氯铵、米拉米斯汀和氯己定相比，CD-1 小鼠口服 5c12 的体内毒性要低得多（LD50 1705 mg/kg）。5c12 (0.2%) 的水溶液在大鼠皮肤模型上显示出与参考药物效率相当。与其他季铵盐一样，5c12 的分子靶标似乎是细胞膜。所获得的结果使所描述的季铵吡哆醇衍生物在开发具有广谱抗菌活性的新型防腐剂方面具有前景和领先分子。与苯扎氯铵、米拉米斯汀和氯己定相比，CD-1 小鼠口服 5c12 的体内毒性要低得多（LD50 1705 mg/kg）。5c12 (0.2%) 的水溶液在大鼠皮肤模型上显示出与参考药物效率相当。与其他季铵盐一样，5c12 的分子靶标似乎是细胞膜。所获得的结果使所描述的季铵吡哆醇衍生物在开发具有广谱抗菌活性的新型防腐剂方面具有前景和领先地位。与苯扎氯铵、米拉米斯汀和氯己定相比，CD-1 小鼠口服 5c12 的体内毒性要低得多（LD50 1705 mg/kg）。5c12 (0.2%) 的水溶液在大鼠皮肤模型上显示出与参考药物效率相当。与其他季铵盐一样，5c12 的分子靶标似乎是细胞膜。所获得的结果使所描述的季铵吡哆醇衍生物在开发具有广谱抗菌活性的新型防腐剂方面具有前景和领先分子。与其他季铵盐一样，5c12 的分子靶标似乎是细胞膜。所获得的结果使所描述的季铵吡哆醇衍生物在开发具有广谱抗菌活性的新型防腐剂方面具有前景和领先分子。与其他季铵盐一样，5c12 的分子靶标似乎是细胞膜。所获得的结果使所描述的季铵吡哆醇衍生物在开发具有广谱抗菌活性的新型防腐剂方面具有前景和领先分子。