Subedi Yagya Prasad, Alfindee Madher N, Shrestha Jaya P, Becker Greg, Grilley Michelle, Takemoto Jon Y, Chang Cheng-Wei Tom
Department of Chemistry and Biochemistry, Utah State University, 0300 Old Main Hill, Logan, UT 84322-0300, USA.
Department of Chemistry and Biochemistry, Utah State University, 0300 Old Main Hill, Logan, UT 84322-0300, USA; Department of Pharmaceutical Chemistry, College of Pharmacy, University of Basra, Basra, Iraq.
Bioorg Med Chem Lett. 2018 Oct 1;28(18):3034-3037. doi: 10.1016/j.bmcl.2018.08.002. Epub 2018 Aug 2.
Phosphonates, azoles and quinones are pharmacophores found in bioactive compounds. A series of phosphonates conjugated to azoles and quinones with variable carbon chain lengths were synthesized in 3-4 steps with good yield. Antifungal assay of these compounds showed that ethyl protected phosphates have excellent inhibitory activity against phytopathogenic fungus Fusarium graminearum, and the free-base phosphates have good activity against human pathogenic fungi Aspergillus flavus and Candida albicans. Structure- activity relationship (SAR) studies showed activity increases with longer carbon chain length between phosphonate and anthraquinone analogs consisting of azole and quinone moieties. These newly synthesized compounds also have mild antibacterial activities to Gram positive bacteria, including methicillin-resistant Staphylococcus aureus (MRSA). Cytotoxicity analysis of these compounds against HeLa cells reveals that the phosphoric acid analogs are less toxic compared to ethyl protected phosphonates. Three leads compounds have been identified with prominent antifungal activity and low cytotoxicity.
膦酸盐、唑类和醌类是生物活性化合物中发现的药效基团。通过3至4步反应合成了一系列与唑类和醌类共轭且碳链长度可变的膦酸盐，产率良好。对这些化合物的抗真菌试验表明，乙基保护的磷酸盐对植物病原真菌禾谷镰刀菌具有优异的抑制活性，而游离碱磷酸盐对人类病原真菌黄曲霉和白色念珠菌具有良好的活性。构效关系（SAR）研究表明，在由唑类和醌类部分组成的膦酸盐和蒽醌类似物之间，随着碳链长度的增加活性增强。这些新合成的化合物对革兰氏阳性菌也有温和的抗菌活性，包括耐甲氧西林金黄色葡萄球菌（MRSA）。对这些化合物针对HeLa细胞的细胞毒性分析表明，磷酸类似物的毒性比乙基保护的膦酸盐低。已鉴定出三种具有显著抗真菌活性和低细胞毒性的先导化合物。
