Department of Pharmaceutical Organic Chemistry, College of Pharmacy, Al-Azhar University, Cairo, Egypt.
Department of Comparative Pathobiology, College of Veterinary Medicine, Purdue University, West Lafayette, Indiana, United States of America.
PLoS One. 2021 Nov 4;16(11):e0258465. doi: 10.1371/journal.pone.0258465. eCollection 2021.
To minimize the intrinsic toxicity of the antibacterial agent hydrazinyloxadiazole 1, the hydrazine moiety was replaced with ethylenediamine (compound 7). This replacement generated a potent antifungal agent with no antibacterial activity. Notably, use of a 1,2-diaminocyclohexane moiety, as a conformationally-restricted isostere for ethylenediamine, potentiated the antifungal activity in both the cis and trans forms of N-(5-(2-([1,1'-biphenyl]-4-yl)-4-methylthiazol-5-yl)-1,3,4-oxadiazol-2-yl)cyclohexane-1,2-diamine (compounds 16 and 17). Both compounds 16 and 17 were void of any antibacterial activity; nonetheless, they showed equipotent antifungal activity in vitro to that of the most potent approved antifungal agent, amphotericin B. The promising antifungal effects of compounds 16 and 17 were maintained when assessed against an additional panel of 26 yeast and mold clinical isolates, including the Candida auris and C. krusei. Furthermore, compound 17 showed superior activity to amphotericin B in vitro against Candida glabrata and Cryptococcus gattii. Additionally, neither compound inhibited the normal human microbiota, and both possessed excellent safety profiles and were 16 times more tolerable than amphotericin B.
为了最大限度地降低抗菌剂肼基噁二唑 1 的内在毒性，将肼基部分替换为乙二胺（化合物 7）。这种替换生成了一种具有抗真菌活性但没有抗菌活性的强效药物。值得注意的是，使用 1,2-二氨基环己烷部分作为乙二胺的构象受限等排体，增强了 N-（5-（2-（[1,1'-联苯]-4-基）-4-甲基噻唑-5-基）-1,3,4-噁二唑-2-基）环己烷-1,2-二胺（化合物 16 和 17）在顺式和反式两种形式下的抗真菌活性。化合物 16 和 17 均无任何抗菌活性；然而，它们在体外显示出与最有效的批准抗真菌药物两性霉素 B 相当的抗真菌活性。在评估另外 26 种酵母和霉菌临床分离株时，化合物 16 和 17 保持了有希望的抗真菌作用，包括耳念珠菌和克柔念珠菌。此外，化合物 17 在体外对光滑念珠菌和隐球菌属的活性优于两性霉素 B。此外，两种化合物均不抑制正常的人类微生物群，且均具有出色的安全性，其耐受性比两性霉素 B 高 16 倍。
