Fytas George, Zoidis Grigoris, Drakopoulos Antonios, Taylor Martin C, Kelly John M, Tsatsaroni Alexandra, Tsotinis Andrew
Faculty of Pharmacy, Department of Pharmaceutical Chemistry, University of Athens, Panepistimiopolis-Zografou, GR-15771 Athens, Greece.
Department of Chemistry and Molecular Biology, University of Gothenburg, Göteborg SE-412 96, Sweden.
ACS Med Chem Lett. 2024 Jun 6;15(7):1041-1048. doi: 10.1021/acsmedchemlett.4c00111. eCollection 2024 Jul 11.
A series of novel hydroxamic acid derivatives was designed and synthesized, and their growth inhibitory activity against bloodstream form was evaluated. These compounds are based on conformationally constrained, lipophilic, spiro carbocyclic 2,6-diketopiperazine (2,6-DKP) scaffolds and bear a side pharmacophoric functionality that contains an acetohydroxamic acid moiety (CHCONHOH) linked with the imidic nitrogen atom of the 2,6-DKP ring via an acetamido portion [CHCON(R), R = H, CH]. Most of these analogues were active in the midnanomolar to low micromolar range against . . ()-Isobutyl- or ()-benzyl-substitution on the methylene carbon located between the amine nitrogen atom and carbonyl of the 2,6-DKP ring was studied. The effect of the methyl-substitution on the nitrogen atom of the acetamido portion in the side pharmacophoric functionality was also examined. Compounds and , bearing an isobutyl- or benzyl-substituent, respectively, and concurrently a methyl-substituent, were found to be the most potent hydroxamates of this series (IC = 34 and 53 nM, respectively). Both had promising selectivity over the parasite compared to mammalian cells (SI = 940 and 470, respectively). Moreover, an conformational behavior study on hydroxamic acid and its methyl-substituted counterpart was undertaken using NMR spectroscopy and theoretical calculations.
设计并合成了一系列新型异羟肟酸衍生物，并评估了它们对血液型的生长抑制活性。这些化合物基于构象受限的亲脂性螺环碳环2,6-二酮哌嗪（2,6-DKP）支架，并带有一个侧链药效基团功能部分，该部分包含一个通过乙酰胺部分[CHCON(R)，R = H，CH]与2,6-DKP环的亚胺氮原子相连的乙酰氧肟酸部分（CHCONHOH）。这些类似物中的大多数对……在中纳摩尔至低微摩尔范围内具有活性。研究了2,6-DKP环的胺氮原子与羰基之间的亚甲基碳上的（）-异丁基或（）-苄基取代情况。还考察了侧链药效基团功能部分中乙酰胺部分氮原子上的甲基取代的影响。分别带有异丁基或苄基取代基且同时带有甲基取代基的化合物和，被发现是该系列中最有效的异羟肟酸酯（IC分别为34和53 nM）。与哺乳动物细胞相比，两者对寄生虫均具有有前景的选择性（SI分别为940和470）。此外，使用核磁共振光谱和理论计算对异羟肟酸及其甲基取代类似物进行了构象行为研究。
