Alves Francinara S, Sousa Abraão P, Almeida-Júnior Alexandre, Lima Priscila S V, Silva Marcelo F R, Galvão José L F M, Lima Edeltrudes O, Souza Helivaldo D S, Luis José A S, Athayde-Filho Petrônio F, Fiss Gabriela F
Laboratório de Pesquisa em Bioenergia e Síntese Orgânica (LPBS), Department of Chemistry, Federal University of Paraíba, João Pessoa 58051-900, Brazil.
Núcleo de Química de Heterociclos (NUQUIMHE), Department of Chemistry, Federal University of Santa Maria, Santa Maria 97105-900, Brazil.
Life (Basel). 2025 Mar 21;15(4):518. doi: 10.3390/life15040518.
Motivated by the search for novel antimicrobials against opportunistic resistant pathogens and based on the reported antimicrobial activity of phthalimides, two series of phthalimide and -phthaloylglycine esters were designed to investigate whether the addition of butyl and aryl groups enhances their antimicrobial properties. Thus, in vitro antimicrobial activity, antifungal mechanism of action, effect combined with Chloramphenicol, in silico/vitro toxicity, and a docking molecular were studied. Phthalimide and -phthaloylglycine aryl esters were obtained in yields of 75-98%. Phthalimide aryl ester (R = Me) showed the best results against Gram-(+) and Gram-(-) bacteria, and , respectively, and yeast fungi, and , with MIC values equal to 128 µg·mL. Regarding the antifungal mechanism of action on , the MIC values of compound changed from 128 to 1024 µg·mL in the presence of ergosterol. Furthermore, compound showed synergy with Chloramphenicol against , with a FICI value equal to 0.5. Finally, the four most promising compounds had their in silico/vitro toxicity evaluated, which showed moderate toxicity to non-toxicity on larvae. With the exception of Chloramphenicol, all selected compounds, including Fluconazole, are potentially hepatotoxic, but they were predicted not to cause skin sensitization, suggesting a potential application for topical use. Molecular docking revealed that compound exhibits superior binding affinity and stability with the 50S ribosomal subunit (-92.69 kcal·mol) compared to Chloramphenicol, and a unique π-sulfur interaction with CYP51, suggesting its potential as a dual-action antibacterial and antifungal candidate against resistant pathogens.
受寻找针对机会性耐药病原体的新型抗菌剂的驱动，并基于邻苯二甲酰亚胺已报道的抗菌活性，设计了两个系列的邻苯二甲酰亚胺和邻苯二甲酰甘氨酸酯，以研究丁基和芳基的添加是否能增强它们的抗菌性能。因此，研究了体外抗菌活性、抗真菌作用机制、与氯霉素联合使用的效果、计算机模拟/体外毒性以及分子对接。邻苯二甲酰亚胺和邻苯二甲酰甘氨酸芳基酯的产率为75 - 98%。邻苯二甲酰亚胺芳基酯（R = 甲基）对革兰氏阳性菌和革兰氏阴性菌分别显示出最佳结果，对酵母真菌也有较好效果，其最低抑菌浓度（MIC）值等于128 µg·mL。关于对[具体真菌名称未给出]的抗真菌作用机制，在麦角固醇存在的情况下，化合物[具体化合物未给出]的MIC值从128变为1024 µg·mL。此外，化合物[具体化合物未给出]与氯霉素对[具体细菌名称未给出]显示出协同作用，协同指数（FICI）值等于0.5。最后，对四种最有前景的化合物进行了计算机模拟/体外毒性评估，结果显示对[具体生物名称未给出]幼虫具有中等毒性至无毒性。除氯霉素外，所有选定的化合物，包括氟康唑，都有潜在的肝毒性，但预计不会引起皮肤致敏，表明它们有局部应用的潜力。分子对接显示，与氯霉素相比，化合物[具体化合物未给出]与50S核糖体亚基具有更高的结合亲和力和稳定性（-92.69 kcal·mol），并且与CYP51有独特的π-硫相互作用，表明其作为针对耐药病原体的双作用抗菌和抗真菌候选药物的潜力。
