Department of Pharmaceutical Chemistry, Faculty of Pharmacy, University of Alexandria, Alexandria, Egypt.
Department of Pharmaceutical Chemistry, Faculty of Pharmacy & Drug Manufacturing, Pharos University in Alexandria, Alexandria, Egypt.
Arch Pharm (Weinheim). 2019 Oct;352(10):e1900086. doi: 10.1002/ardp.201900086. Epub 2019 Aug 7.
Antibiotic-resistant bacteria continue to play an important role in human health and disease. Inventive strategies are necessary to develop new therapeutic leads to challenge drug-resistance problems. From this perception, new quinoline hybrids bearing bioactive pharmacophores were synthesized. The newly synthesized compounds were evaluated for their in vitro antibacterial activity against nine bacterial pathogenic strains. The results revealed that most compounds exhibited good antibacterial activities. Seven compounds (2b, 3b, 4, 6, 8b, and 9c,d) displayed enhanced activity against methicillin-resistant Staphylococcus aureus compared to ampicillin. These compounds were subjected to an in vitro S. aureus DNA gyrase ATPase inhibition study, which revealed that compounds 8b, 9c, and 9d showed the highest inhibitory activity with IC values of 1.89, 2.73, and 2.14 μM, respectively, comparable to novobiocin (IC , 1.636 μM). Compounds 2a-c, 3a, 7c, 9c,d, and 10a,b revealed half the potency of levofloxacin in inhibiting the growth of Pseudomonas aeruginosa. As an attempt to rationalize the observed antibacterial activity for the most active compounds 8b, 9c, and 9d, molecular docking in the ATP binding site of S. aureus gyrase B was performed using Glide. Such compounds could be considered as promising scaffolds for the development of new potent antibacterial agents.
耐药菌继续在人类健康和疾病中发挥重要作用。有必要发明创新策略来开发新的治疗方法以应对耐药性问题。基于这一认识，我们合成了具有生物活性药效团的新型喹啉杂合体。新合成的化合物进行了体外抗菌活性评估，以评估它们对 9 种细菌病原体的抑制作用。结果表明，大多数化合物具有良好的抗菌活性。与氨苄西林相比，7 种化合物（2b、3b、4、6、8b 和 9c、d）对耐甲氧西林金黄色葡萄球菌表现出增强的活性。这些化合物进行了体外金黄色葡萄球菌 DNA 拓扑异构酶 ATP 酶抑制研究，结果表明化合物 8b、9c 和 9d 表现出最高的抑制活性，IC 值分别为 1.89、2.73 和 2.14μM，与诺氟沙星（IC 50 ，1.636μM）相当。化合物 2a-c、3a、7c、9c、d 和 10a、b 对抑制铜绿假单胞菌生长的左氧氟沙星的效力减半。为了合理解释最活跃的化合物 8b、9c 和 9d 的观察到的抗菌活性，使用 Glide 在金黄色葡萄球菌拓扑异构酶 B 的 ATP 结合位点进行了分子对接。这些化合物可以被认为是开发新型有效抗菌剂的有前途的支架。
