Design, synthesis and biological evaluation of 8-hydroxyquinoline derivatives as potential clostridium difficile antibiotics

YE Tengfei; CHENG Tao; SONG Ping; JI Weili; BIAN Xiaolan

doi:10.12206/j.issn.2097-2024.202303021

Objective To find a more effective alternative therapy for antibiotic therapy and fecal microbiota transplantation in current primary treatment of clostridioides difficile infection (CDI) because of the high recurrence rate. Methods A series of 8-hydroxyquinoline derivatives were designed and synthesized based on 8-hydroxyquinoline scarffold. Results The activity test against C. difficile showed that most of the molecules exhibited good antibacterial activity against C. difficile, and compound 6 f showed attractive anti-C. difficile activity. Conclusion A new type of 8-hydroxyquinoline derivatives with anti-clostridium difficile was found, which could be used as good lead compounds for further development.

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艰难梭菌的感染率近年来有所提高^[1]，其孢子很难根除，并且很容易通过医护人员传播，是医院、养老院和一些健康护理机构出现腹泻感染的原因之一^[2]。目前针对艰难梭菌的可用治疗方法都有一些缺点，例如成本过高、耐药性的发展和选择性问题。虽然轻度至中度的艰难梭菌病例目前可以通过可用的治疗方法进行控制，但对严重的病例可能需要使用单一常规药物或联合疗法进行长期抑制治疗，如果不成功，则要采用非常规和(或)侵入性的手段，如粪便移植和结肠切除术^[3]。因此，临床上对药物研发需求越来越大，寻求一种更有效的替代疗法迫在眉睫^[1]。

含有喹啉的杂芳族化合物具有多种生物和药理活性，例如，抗疟疾^[4]、抗结核病^[5]、抗炎^[6]、抗癌^[7]、抗高血压^[8]以及抗菌^[9-11]。Musiol 等^[12]曾报道 8-羟基喹啉衍生物的抗真菌活性。此外，8-羟基喹啉衍生物显示出对神经退行性疾病如阿尔茨海默病良好活性^[13]。最近，研究发现8-羟基喹啉衍生物具有抗金黄色葡萄球菌的潜在作用^[14]。我们的小组最近通过药物数据库筛选发现，溴氧喹啉（5,7-二溴喹啉-8-酚）对艰难梭菌具有强效抗菌活性。基于此有前景的化合物，我们进行了一系列8-羟基喹啉类似物的设计、合成和抗艰难梭菌活性研究。

3. 结果

3.1. 8-羟基喹啉衍生物的抗艰难梭菌活性评价

所有目标化合物及部分中间体均针对两种菌株 BAA1875 和 R20291 的艰难梭菌进行了活性测试。基于生物活性（见表1），SAR总结如下：①8位的游离羟基对艰难梭菌的抑制活性起着非常重要的作用，其甲基化会大幅降低活性（化合物1和3c分别对BAA-1875为大于256 μg/ml）。② 6 位的取代对于活性很重要，体积大的基团（例如萘基）对活性有利（萘基 6f > 苯基 6a ）。此外，对于 6 位萘取代的化合物，2-萘基优于1-萘基（6f vs 6h），且带有 OH 或 OCH₃ 取代基的萘环也会降低活性（5b-c, 6i-j）。③对于6位杂环取代的类似物，引入杂原子后会导致活性整体下降，且六六并环（ 8a-c ）的活性显著好于五六并环（ 8d-h ）。 ④对于7位的替换，大基团对活性不利。溴原子是最佳取代，随着取代基大小的增加，活性略有下降（9>11b>11a）。 ⑤5 位苯环取代依旧可以保持活性（13）。

化合物	BAA 1875^a	R20291^a	化合物	BAA 1875^a	R20291^a
1	>256	>256	8a	4	2
3c	>256	>256	8b	8	8
5a	4	2	8c	8	4
5b	32	32	8d	>256	>256
5c	8	8	8e	>256	>256
6a	1	4	8f	32	32
6b	1	4	8g	64	32
6c	>256	>256	8h	64	16
6d	>256	>256	8i	32	32
6e	8	8	9	0.5	0.25
6f	0.5	0.25	11a	4	4
6g	2	2	11b	2	1
6h	8	4	13	0.5	0.25
6i	16	8	万古霉素	0.25	0.125
6j	16	16
注：a.化合物起始浓度256 µg/ml

3.2. 部分8-羟基喹啉衍生物的MIC和MBC测试结果

进一步测试了部分8-羟基喹啉衍生物针对艰难梭菌R20291的最小杀菌浓度（MBC）（表2），所测试化合物的最小杀菌浓度（MBC）和MIC相当，表明这些化合物能够有效地杀死艰难梭菌，具有更强的抑菌作用。在这些化合物中，化合物 6f 表现出良好的活性，这使其成为可进一步开发的良好先导化合物。

化合物 R20291

MIC MBC

5a 3.2 3.2

6e 6.4 6.4

6f 0.1 0.2

6h 3.2 3.2

9 0.1 0.2

11a 3.2 3.2

13 0.4 0.4

4. 讨论

基于重要的抗艰难梭菌骨架8-羟基喹啉，我们设计并合成了一系列8-羟基喹啉衍生物，所有目标化合物均经过了核磁和质谱确证结构，纯度均高于95%。针对艰难梭菌菌株BAA1875和R20291的抑菌试验显示，多个化合物具有强效的抑菌作用，且MIC 与MBC 非常接近，表明这些化合物还具有强效的杀菌作用。这使它们成为可进一步开发的良好先导化合物，后续的结构优化工作尚在进行之中。

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Design, synthesis and biological evaluation of 8-hydroxyquinoline derivatives as potential clostridium difficile antibiotics

doi: 10.12206/j.issn.2097-2024.202303021

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通讯作者: 陈斌, bchen63@163.com

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