Department of Organic Chemistry, Kaunas University of Technology, Radvilėnų Rd. 19, 50254 Kaunas, Lithuania.
Transplantation-Oncology Infectious Diseases Program, Division of Infectious Diseases, Department of Medicine, Weill Cornell Medicine of Cornell University, 1300 York Ave., New York, NY 10065, USA.
Int J Mol Sci. 2023 Apr 27;24(9):7966. doi: 10.3390/ijms24097966.
Increasing antimicrobial resistance among Gram-positive pathogens and pathogenic fungi remains one of the major public healthcare threats. Therefore, novel antimicrobial candidates and scaffolds are critically needed to overcome resistance in Gram-positive pathogens and drug-resistant fungal pathogens. In this study, we explored 1-(2-hydroxyphenyl)-5-oxopyrrolidine-3-carboxylic acid and its 3,5-dichloro-2-hydroxyphenyl analogue for their in vitro antimicrobial activity against multidrug-resistant pathogens. The compounds showed structure-dependent antimicrobial activity against Gram-positive pathogens (, , ). Compounds and showed promising activity against vancomycin-intermediate strains, and favorable cytotoxic profiles in HSAEC-1 cells, making them attractive scaffolds for further development. 5-Fluorobenzimidazole, having a 3,5-dichloro-2-hydroxyphenyl substituent, was found to be four-fold, and hydrazone, with a thien-2-yl fragment, was two-fold stronger than clindamycin against methicillin resistant TCH 1516. Moreover, hydrazone, bearing a 5-nitrothien-2-yl moiety, showed promising activity against three tested multidrug-resistant isolates representing major genetic lineages (MIC 16 µg/mL) and azole-resistant strains harboring TR34/L98H mutations in the CYP51A gene. The anticancer activity characterization demonstrated that the 5-fluorobenzimidazole derivative with a 3,5-dichloro-2-hydroxyphenyl substituent showed the highest anticancer activity in an A549 human pulmonary cancer cell culture model. Collectively these results demonstrate that 1-(2-hydroxyphenyl)-5-oxopyrrolidine-3-carboxylic acid derivatives could be further explored for the development of novel candidates targeting Gram-positive pathogens and drug-resistant fungi.
革兰氏阳性病原体和致病性真菌的抗菌药物耐药性不断增加仍然是主要的公共卫生保健威胁之一。因此，迫切需要新型抗菌候选物和支架来克服革兰氏阳性病原体和耐药真菌病原体的耐药性。在这项研究中，我们探索了 1-(2-羟基苯基)-5-氧代吡咯烷-3-羧酸及其 3,5-二氯-2-羟基苯基类似物对多药耐药病原体的体外抗菌活性。这些化合物表现出结构依赖性的抗革兰氏阳性病原体活性（金黄色葡萄球菌、表皮葡萄球菌和屎肠球菌）。化合物和表现出对万古霉素中介金黄色葡萄球菌菌株的有前景的活性，并且在 HSAEC-1 细胞中具有良好的细胞毒性特征，使它们成为进一步开发的有吸引力的支架。具有 3,5-二氯-2-羟基苯基取代基的 5-氟苯并咪唑被发现比克林霉素对耐甲氧西林金黄色葡萄球菌 TCH 1516 的抑制作用强四倍，而具有噻吩-2-基片段的腙则强两倍。此外，具有 5-硝基噻吩-2-基部分的腙对三种测试的多药耐药分离株表现出有希望的活性，这些分离株代表主要遗传谱系（MIC 16 µg/mL），并且携带 CYP51A 基因中的 TR34/L98H 突变的唑类耐药菌株。抗癌活性特征表明，具有 3,5-二氯-2-羟基苯基取代基的 5-氟苯并咪唑衍生物在 A549 人肺癌细胞培养模型中表现出最高的抗癌活性。总之，这些结果表明 1-(2-羟基苯基)-5-氧代吡咯烷-3-羧酸衍生物可以进一步探索用于开发针对革兰氏阳性病原体和耐药真菌的新型候选物。
