Priebbenow Daniel L, Mathiew Mitch, Shi Da-Hua, Harjani Jitendra R, Beveridge Julia G, Chavchich Marina, Edstein Michael D, Duffy Sandra, Avery Vicky M, Jacobs Robert T, Brand Stephen, Shackleford David M, Wang Wen, Zhong Longjin, Lee Given, Tay Erin, Barker Helena, Crighton Elly, White Karen L, Charman Susan A, De Paoli Amanda, Creek Darren J, Baell Jonathan B
School of Chemistry, The University of Melbourne, Parkville, VIC 3010, Australia.
Medicinal Chemistry, Monash Institute of Pharmaceutical Sciences, Monash University (Parkville Campus), 381 Royal Parade, Parkville, VIC 3052, Australia.
J Med Chem. 2021 Apr 8;64(7):4150-4162. doi: 10.1021/acs.jmedchem.1c00044. Epub 2021 Mar 24.
Novel 3,3'-disubstituted-5,5'-bi(1,2,4-triazine) compounds with potent activity against parasites were recently discovered. To improve the pharmacokinetic properties of the triazine derivatives, a new structure-activity relationship (SAR) investigation was initiated with a focus on enhancing the metabolic stability of lead compounds. These efforts led to the identification of second-generation highly potent antimalarial bis-triazines, exemplified by triazine , which exhibited significantly improved metabolic stability (8 and 42 μL/min/mg protein in human and mouse liver microsomes). The disubstituted triazine dimer was also observed to suppress parasitemia in the Peters 4-day test with a mean ED value of 1.85 mg/kg/day and exhibited a fast-killing profile, revealing a new class of orally available antimalarial compounds of considerable interest.
最近发现了对寄生虫具有强效活性的新型3,3'-二取代-5,5'-联（1,2,4-三嗪）化合物。为改善三嗪衍生物的药代动力学性质，开展了一项新的构效关系（SAR）研究，重点是提高先导化合物的代谢稳定性。这些努力导致鉴定出第二代高效抗疟双三嗪，以三嗪为例，其代谢稳定性显著提高（在人和小鼠肝微粒体中分别为8和42 μL/min/mg蛋白）。在彼得斯4天试验中还观察到二取代三嗪二聚体抑制疟原虫血症，平均ED值为1.85 mg/kg/天，并呈现快速杀灭特征，揭示了一类具有相当吸引力的口服可用抗疟化合物。
