Saczewski Jaroslaw, Fedorowicz Joanna, Kedzia Anna, Ziolkowska-Klinkosz Marta, Jalinska Aleksandra
Department of Organic Chemistry, Medical University of Gdansk, Al. Gen. J. Hallera 107, 80-416, Gdansk, Poland.
Med Chem. 2016;12(7):640-646. doi: 10.2174/1573406412666160517122925.
Cutaneous and invasive fungal infections are constant threats to human health that substantiate the need for the development of new efficacious and safe antimycotics.
A series of N1-alkyl, N1-acyl and N1-sulfonyl derivatives of 4,6- dimethylisoxazolo[3,4-b]pyridin-3(1H)-one (1) were synthesized. The antimicrobial activities of title compounds against 21 pathogenic yeast-like fungal clinical isolates and 5 reference strains were evaluated by means of a broth microdilution method.
Among the compounds tested, the newly prepared N1-benzoyl (2m) and N1-(4-fluorobenzoyl) (2n) derivatives of 1 showed 81% and 95% inhibitory efficacy, respectively, against the clinical isolates, which were comparable to that of the reference drug fluconazole. The strains that exhibited the highest susceptibility to the compound 2n included Candida utilis (MIC < 6.2 μg/mL), C. parapsilosis (MIC in the range <6.2 - 12.5 μg/mL), Geotrichum candidum (MIC = 12.5 μg/mL) as well as C. lusitaniae and Rhodotorula mucilaginosa (MIC = 25 μg/mL).
In terms of MIC, compound 2n proved to be four times more active against the clinical isolates of Candida albicans and C. albicans ATCC 10231 standard strain than fluconazole, the widely prescribed antifungal agent for mucosal and systemic yeast infections (MIC = 50 vs 200 μg/mL).
皮肤和侵袭性真菌感染一直威胁着人类健康，这证实了开发新型高效且安全的抗真菌药物的必要性。
合成了一系列4,6-二甲基异恶唑并[3,4-b]吡啶-3(1H)-酮（1）的N1-烷基、N1-酰基和N1-磺酰基衍生物。采用肉汤微量稀释法评估了标题化合物对21株致病性酵母样真菌临床分离株和5株参考菌株的抗菌活性。
在所测试的化合物中，新制备的1的N1-苯甲酰基（2m）和N1-(4-氟苯甲酰基)（2n）衍生物对临床分离株的抑制效果分别为81%和95%，与参考药物氟康唑相当。对化合物2n表现出最高敏感性的菌株包括产朊假丝酵母（MIC < 6.2 μg/mL）、近平滑假丝酵母（MIC范围<6.2 - 12.5 μg/mL）、白地霉（MIC = 12.5 μg/mL）以及葡萄牙假丝酵母和粘红酵母（MIC = 25 μg/mL）。
就最低抑菌浓度而言，化合物2n对白色念珠菌临床分离株和白色念珠菌ATCC 10231标准菌株的活性比广泛用于黏膜和全身性酵母菌感染的抗真菌药物氟康唑高四倍（MIC = 50对200 μg/mL）。
