Kokkonda Sreekanth, El Mazouni Farah, White Karen L, White John, Shackleford David M, Lafuente-Monasterio Maria Jose, Rowland Paul, Manjalanagara Krishne, Joseph Jayan T, Garcia-Pérez Adolfo, Fernandez Jorge, Gamo Francisco Javier, Waterson David, Burrows Jeremy N, Palmer Michael J, Charman Susan A, Rathod Pradipsinh K, Phillips Margaret A
Departments of Chemistry and Global Health, University of Washington, Seattle, Washington 98195, United States.
Department of Biochemistry, University of Texas Southwestern Medical Center at Dallas, 5323 Harry Hines Blvd, Dallas, Texas 75390-9038, United States.
ACS Omega. 2018 Aug 31;3(8):9227-9240. doi: 10.1021/acsomega.8b01573. Epub 2018 Aug 15.
Malaria kills nearly 0.5 million people yearly and impacts the lives of those living in over 90 countries where it is endemic. The current treatment programs are threatened by increasing drug resistance. Dihydroorotate dehydrogenase (DHODH) is now clinically validated as a target for antimalarial drug discovery as a triazolopyrimidine class inhibitor () is currently undergoing clinical development. We discovered a related isoxazolopyrimidine series in a phenotypic screen, later determining that it targeted DHODH. To determine if the isoxazolopyrimidines could yield a drug candidate, we initiated hit-to-lead medicinal chemistry. Several potent analogues were identified, including a compound that showed in vivo antimalarial activity. The isoxazolopyrimidines were more rapidly metabolized than their triazolopyrimidine counterparts, and the pharmacokinetic data were not consistent with the goal of a single-dose treatment for malaria.
疟疾每年导致近50万人死亡，并影响着90多个疟疾流行国家中人们的生活。目前的治疗方案正受到耐药性增加的威胁。二氢乳清酸脱氢酶（DHODH）现已在临床上被确认为抗疟药物研发的靶点，因为一种三唑并嘧啶类抑制剂目前正在进行临床开发。我们在一个表型筛选中发现了一个相关的异恶唑并嘧啶系列，后来确定它靶向DHODH。为了确定异恶唑并嘧啶是否能产生一种候选药物，我们启动了从苗头化合物到先导化合物的药物化学研究。我们鉴定出了几种强效类似物，其中一种化合物显示出体内抗疟活性。异恶唑并嘧啶的代谢速度比其对应的三唑并嘧啶更快，其药代动力学数据与疟疾单剂量治疗的目标不一致。
