Omara Mariam, Hagras Mohamed, Elsebaie Mohamed M, Abutaleb Nader S, Nour El-Din Hanzada T, Mekhail Maria O, Attia Ahmed S, Seleem Mohamed N, Sarg Marwa T, Mayhoub Abdelrahman S
Department of Pharmaceutical Organic Chemistry, College of Pharmacy (Girls), Al-Azhar University Cairo Egypt.
Department of Pharmaceutical Organic Chemistry, College of Pharmacy (Boys), Al-Azhar University Cairo 11884 Egypt
RSC Adv. 2023 Jul 6;13(29):19695-19709. doi: 10.1039/d3ra02778c. eCollection 2023 Jun 29.
Antimicrobial resistance has become a concern as a worldwide threat. A novel scaffold of phenylthiazoles was recently evaluated against multidrug-resistant to control the emergence and spread of antimicrobial resistance, showing good results. Several structural modifications are needed based on the structure-activity relationships (SARs) of this new antibiotic class. Previous studies revealed the existence of two key structural features essential for the antibacterial activity, the guanidine head and lipophilic tail. In this study, a new series of twenty-three phenylthiazole derivatives were synthesized utilizing the Suzuki coupling reaction to explore the lipophilic part. The antibacterial activity was evaluated against a range of clinical isolates. The three most promising compounds, 7d, 15d and 17d, with potent MIC values against MRSA USA300 were selected for further antimicrobial evaluation. The tested compounds exhibited potent results against the tested MSSA, MRSA, and VRSA strains (concentration: 0.5 to 4 μg mL). Compound 15d inhibited MRSA USA400 at a concentration of 0.5 μg mL (one-fold more potent than vancomycin) and showed low MIC values against ten clinical isolates, including linezolid-resistant strain MRSA NRS119 and three vancomycin-resistant isolates VRSA 9/10/12. Moreover, compound 15d retained its potent antibacterial activity using the model by the burden reduction of MRSA USA300 in skin-infected mice. The tested compounds also showed good toxicity profiles and were found to be highly tolerable to Caco-2 cells at concentrations of up to 16 μg mL, with 100% of the cells remaining viable.
抗菌耐药性已成为一个全球性威胁，令人担忧。最近对一种新型苯并噻唑支架针对多重耐药性进行了评估，以控制抗菌耐药性的出现和传播，结果良好。基于这一新抗生素类别的构效关系（SARs），需要进行一些结构修饰。先前的研究揭示了抗菌活性所必需的两个关键结构特征，即胍基头部和亲脂性尾部。在本研究中，利用铃木偶联反应合成了一系列23种新的苯并噻唑衍生物，以探索亲脂性部分。针对一系列临床分离株评估了抗菌活性。选择了对美国300型耐甲氧西林金黄色葡萄球菌（MRSA）具有有效最低抑菌浓度（MIC）值的三种最有前景的化合物7d、15d和17d进行进一步的抗菌评估（浓度：0.5至4μg/mL）。测试的化合物对测试的甲氧西林敏感金黄色葡萄球菌（MSSA）、耐甲氧西林金黄色葡萄球菌（MRSA）和耐万古霉素金黄色葡萄球菌（VRSA）菌株显示出有效的结果。化合物15d在浓度为0.5μg/mL时抑制美国400型耐甲氧西林金黄色葡萄球菌（MRSA USA400）（比万古霉素强一倍），并且对十种临床分离株显示出低MIC值，包括耐利奈唑胺菌株MRSA NRS119和三种耐万古霉素分离株VRSA 9/10/12。此外，通过降低皮肤感染小鼠体内美国300型耐甲氧西林金黄色葡萄球菌（MRSA USA300）的负荷模型，化合物15d保留了其强大的抗菌活性。测试的化合物还显示出良好的毒性特征，并且发现在浓度高达16μg/mL时对Caco-2细胞具有高度耐受性，100%的细胞保持存活。
