School of Chemistry and Chemical Engineering, Southwest University, Chongqing, 400715, PR China.
School of Chemistry and Chemical Engineering, Southwest University, Chongqing, 400715, PR China.
Eur J Med Chem. 2020 Jun 1;195:112278. doi: 10.1016/j.ejmech.2020.112278. Epub 2020 Apr 4.
A series of 3,4-dihydro-2(1H)-quinolinone derivatives contained butenediamide fragment were designed and synthesized. Their inhibition potency against chitin synthase and antimicrobial activities were screened in vitro. The enzymatic assays showed that all the synthesized compounds had inhibition potency against chitin synthase at concentration of 300 μg/mL. Compound 2d displayed excellent potency with inhibition percentage (IP) value of 82.3%, while IP value of the control polyoxin B was 87.5%. Compounds 2b, 2e and 2s whose IP values were above 70% showed good inhibition potency against chitin synthase. Moreover, the IC value of 2b was comparable with that of polyoxin B (0.09 mM). The K of compound 2b was 0.12 mM and the result from Lineweaver-Burk plot showed that 2b was non-competitive inhibitor to bind chitin synthase. The antifungal experiment showed that these compounds had excellent antifungal activity against fungal strains, especially for candida albicans. The antifungal activities against C .albicans of compounds 2b, 2d, 2e and 2l were comparable with that of fluconazole and were superior to that of polyoxin B. Meanwhile, the other compounds against C. albicans showed better antifungal activity (MIC 2 μg/mL) than polyoxin B except for compound 2n (MIC 4 μg/mL). The trial of drug combination use showed that these synthesized compounds had synergistic effects with fluconazole and polyoxin B. It indicated that these compounds were not competing with polyoxin B to bind with chitin synthase, which was also consistence with the result of enzymatic assays. The antibacterial experiment showed that these compounds had no activity against selected strains including three Gram-positive and three Gram-negative bacteria. These results showed that the designed compounds were chitin synthase inhibitors and had selective antifungal activity.
一系列含有丁二酰胺片段的 3,4-二氢-2(1H)-喹啉酮衍生物被设计和合成。在体外筛选了它们对几丁质合酶的抑制活性和抗菌活性。酶活性测定结果表明，所有合成的化合物在 300μg/mL 浓度下均对几丁质合酶具有抑制活性。化合物 2d 表现出优异的活性，抑制率（IP）值为 82.3%，而对照多氧菌素 B 的 IP 值为 87.5%。IP 值高于 70%的化合物 2b、2e 和 2s 对几丁质合酶表现出良好的抑制活性。此外，2b 的 IC 值与多氧菌素 B 相当（0.09 mM）。2b 的 K 值为 0.12 mM，Lineweaver-Burk 作图结果表明 2b 是非竞争性抑制剂与几丁质合酶结合。抗真菌实验表明，这些化合物对真菌菌株具有优异的抗真菌活性，特别是对白色念珠菌。化合物 2b、2d、2e 和 2l 对白色念珠菌的抗真菌活性与氟康唑相当，优于多氧菌素 B。同时，除化合物 2n（MIC 4μg/mL）外，其他化合物对白色念珠菌的抗真菌活性（MIC 2μg/mL）优于多氧菌素 B。药物联合使用试验表明，这些合成化合物与氟康唑和多氧菌素 B 具有协同作用。这表明这些化合物与多氧菌素 B 竞争结合几丁质合酶，这与酶活性测定的结果一致。抗菌实验表明，这些化合物对所选菌株（包括三种革兰氏阳性菌和三种革兰氏阴性菌）均无活性。这些结果表明，设计的化合物是几丁质合酶抑制剂，具有选择性抗真菌活性。
