Ravu Ranga Rao, Jacob Melissa R, Khan Shabana I, Wang Mei, Cao Liang, Agarwal Ameeta K, Clark Alice M, Li Xing-Cong
National Center for Natural Products Research, Research Institute of Pharmaceutical Sciences, The University of Mississippi, University, Mississippi 38677, United States.
Department of BioMolecular Sciences, School of Pharmacy, The University of Mississippi, University, Mississippi 38677, United States.
J Nat Prod. 2021 Aug 27;84(8):2129-2137. doi: 10.1021/acs.jnatprod.1c00116. Epub 2021 Jul 20.
The phloeodictine-based 6-hydroxy-2,3,4,6-tetrahydropyrrolo[1,2-]pyrimidinium structural moiety with an -tetradecyl side chain at C-6 has been demonstrated to be a new antifungal template. Thirty-four new synthetic analogues with modifications of the bicyclic tetrahydropyrrolopyrimidinium skeleton and the N-1 side chain have been prepared and evaluated for in vitro antifungal activities against the clinically important fungal pathogens including ATCC 90113, ATCC 90028, ATCC 90030, ATCC 6258, and ATCC 90906. Nineteen compounds (, -, -, , and ) showed antifungal activities against the aforementioned five fungal pathogens with minimum inhibitory concentrations (MICs) in the range 0.88-10 μM, and all were fungicidal with minimum fungicidal concentrations (MFCs) similar to the respective MIC values. Compounds , , and were especially active against ATCC 90113 with MIC/MFC values of 1.0/1.0, 1.6/1.6, and 1.3/2.0 μM but exhibited low cytotoxicity with an IC > 40 μM against the mammalian Vero cells. The structure and antifungal activity relationship indicates that synthetic modifications of the phloeodictines can afford analogues with potent antifungal activity and reduced cytotoxicity, necessitating further preclinical studies of this new class of antifungal compounds.
已证明，在C-6位带有十四烷基侧链的基于根皮啶的6-羟基-2,3,4,6-四氢吡咯并[1,2 - ]嘧啶结构部分是一种新的抗真菌模板。已制备了34种对双环四氢吡咯并嘧啶骨架和N-1侧链进行修饰的新合成类似物，并对其针对包括ATCC 90113、ATCC 90028、ATCC 90030、ATCC 6258和ATCC 90906在内的临床上重要的真菌病原体的体外抗真菌活性进行了评估。19种化合物（， - ， - ， ，和 ）对上述5种真菌病原体表现出抗真菌活性，其最低抑菌浓度（MIC）范围为0.88 - 10 μM，并且所有化合物均具有杀菌作用，其最低杀菌浓度（MFC）与各自的MIC值相似。化合物 ， 和 对ATCC 90113特别有活性，其MIC / MFC值为1.0 / 1.0、1.6 / 1.6和1.3 / 2.0 μM，但对哺乳动物Vero细胞的细胞毒性较低，IC> 40 μM。结构与抗真菌活性关系表明，根皮啶的合成修饰可以提供具有强效抗真菌活性和降低细胞毒性的类似物，因此需要对这类新型抗真菌化合物进行进一步的临床前研究。
