Poyraz Yılmaz Pınar, Kulabaş Necla, Bozdeveci Arif, Vagolu Siva Krishna, Imran Mohd, Tatar Esra, Alpay Karaoğlu Şengül, Sriram Dharmarajan, Mahmood Ammar A Razzak, Küçükgüzel İlkay
Institute of Health Sciences, Marmara University, İstanbul, Turkey.
Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Marmara University, İstanbul, Turkey.
Chem Biol Drug Des. 2025 May;105(5):e70126. doi: 10.1111/cbdd.70126.
Twenty azole-fluoroquinolone hybrids were designed and synthesized by conjugating thiazole and thiadiazole structures to ciprofloxacin and norfloxacin via a 2-oxoethyl bridge. The structures and purities of the synthesized compounds were proven by spectral techniques. The antimycobacterial effects of target compounds 21-40 were tested against Mycobacterium tuberculosis H37Rv strain. Among the 20 synthesized compounds, 12 exhibited minimal inhibition concentration (MIC) values in the range of 1.56-25 μg/mL. Among the molecules screened for antimycobacterial effects, the most effective was compound 35, a thiadiazole-ciprofloxacin hybrid. The cytotoxic effect of this molecule was found to be lower than the reference drugs, and it was also determined to be a more effective inhibitor than ciprofloxacin and norfloxacin in the DNA-gyrase supercoiling test. The antimicrobial effects of compounds 21-40 were screened by agar-well diffusion and microdilution tests against Gram-positive/negative bacteria, a fast-growing mycobacterium, and two yeast strains. While most of the compounds tested showed antibacterial effects, the most effective fluoroquinolone derivative appeared to be compound 31 with an MIC value of < 0.63 μg/mL against all Gram-negative bacteria tested. Azole-fluoroquinolone hybrids 21-40 did not show any activity against non-pathogenic Lactobacillus species and yeast-like fungi, indicating that they have selective antibacterial and antimycobacterial activity, particularly against Gram-negative bacteria. In silico molecular docking studies were conducted to uncover the interactions between lead compound 35 and the DNA gyrase proteins of M. tuberculosis and S. aureus. Additionally, a 100 ns molecular dynamics simulation was carried out to assess the stability of the complexes formed between compound 35 and both proteins.
通过2-氧代乙基桥将噻唑和噻二唑结构与环丙沙星和诺氟沙星共轭，设计并合成了20种唑类-氟喹诺酮杂化物。通过光谱技术证实了合成化合物的结构和纯度。测试了目标化合物21-40对结核分枝杆菌H37Rv菌株的抗分枝杆菌作用。在20种合成化合物中，12种的最低抑菌浓度（MIC）值在1.56-25μg/mL范围内。在筛选抗分枝杆菌作用的分子中，最有效的是化合物35，一种噻二唑-环丙沙星杂化物。发现该分子的细胞毒性作用低于参考药物，并且在DNA促旋酶超螺旋试验中也被确定为比环丙沙星和诺氟沙星更有效的抑制剂。通过琼脂孔扩散和微量稀释试验，筛选了化合物21-40对革兰氏阳性/阴性细菌、一种快速生长的分枝杆菌和两种酵母菌株的抗菌作用。虽然大多数测试化合物显示出抗菌作用，但最有效的氟喹诺酮衍生物似乎是化合物31，其对所有测试革兰氏阴性细菌的MIC值<0.63μg/mL。唑类-氟喹诺酮杂化物21-40对非致病性乳酸杆菌属和酵母样真菌没有任何活性，表明它们具有选择性抗菌和抗分枝杆菌活性，特别是对革兰氏阴性细菌。进行了计算机模拟分子对接研究，以揭示先导化合物35与结核分枝杆菌和金黄色葡萄球菌的DNA促旋酶蛋白之间的相互作用。此外，进行了100 ns的分子动力学模拟，以评估化合物35与两种蛋白质形成的复合物的稳定性。
