为了开发抗病毒药物,我们利用蝶呤酸(Poa-1)作为先导化合物,并进行了各种修饰,包括氧化,reduction,addition,酯化,和酰化,合成了29种衍生物,其中25个是新的酰化衍生物。细胞水平验证表明,4种衍生物对甲型流感病毒(H1N1)表现出显著的抑制作用,IC50=4.04-36.13μM。值得注意的是,四种酰化衍生物(化合物IIE5,IIE6,IIE9和IIE17)表现出针对甲型流感病毒(H1N1)的特异性抗病毒活性,具有低细胞毒性,表明有利的治疗指数(SI=3.5-11.9)。构效关系研究表明,C5-C6烯烃是抗病毒活性的必需基团,C11-C12共轭烯烃不会干扰抗病毒活性。羧酸是活性的必需基团。此外,羧酸酰化可以提高抗病毒活性,包括胍,环胺,和带有给电子取代基的苯基可以增强先导化合物的抗病毒活性。天然产物结构修饰能够提高先导化合物的生物活性,为开发有效的新结构提供了一条快速的途径。
In order to develop antiviral drugs, we utilized pterodontic acid (Poa-1) as a lead compound and conducted various modifications, including oxidation, reduction, addition, esterification, and
acylation, resulting in the synthesis of 29 derivatives, of which 25 were novel
acylation derivatives. Cell-level validation demonstrated that 4 derivatives exhibited significant inhibitory effects on the influenza A virus (H1N1), with an IC50 = 4.04-36.13 μM. Notably, four
acylation derivatives (compounds IIE5, IIE6, IIE9, and IIE17) exhibited specific antiviral activities against influenza A virus (H1N1) with low cytotoxicity, indicating favorable therapeutic indices (SI = 3.5-11.9). Structure-activity relationship studies indicated that C5-C6 olefins are essential groups for antiviral activity, C11-C12 conjugated olefins will not interfere with antiviral activity. Carboxylic acid is an essential group for activity. Moreover,Carboxylic acid
acylation can improve antiviral activity, and the inclusion of guanidine, cyclic amine, and phenyl groups with electron-donating substituents could enhance the antiviral activity of the lead compound. Natural products structural modifications are capable of improving the biological activity of lead compounds, offering a rapid pathway for the development of potent new structures.