Arafa Reem K, Ismail Mohamed A, Munde Manoj, Wilson W David, Wenzler Tanja, Brun Reto, Boykin David W
Department of Chemistry, Center for Biotechnology and Drug Design, Georgia State University, Atlanta, GA 30303-3083, USA.
Eur J Med Chem. 2008 Dec;43(12):2901-8. doi: 10.1016/j.ejmech.2008.02.008. Epub 2008 Feb 29.
A series of triaryl guanidines and N-substituted guanidines designed to target the minor groove of DNA were synthesized and evaluated as antiprotozoal agents. Selected carbamate prodrugs of these guanidines were assayed for their oral efficacy. The linear triaryl bis-guanidines 6a,b were prepared from their corresponding diamines 4a,b through the intermediate BOC protected bis-guanidines 5a,b followed by acid catalyzed deprotection. The N-substituted guanidino analogues 9c-f were obtained in three steps starting by reacting the diamines 4a,b with ethyl isothiocyanatoformate to give the carbamoyl thioureas 7a,b. Subsequent condensation of 7a,b with various amines in the presence of EDCI provided the carbamoyl N-substituted guanidine intermediates 8a-f which can also be regarded as potential prodrugs for the guanidino derivatives. Compounds 9c-f were obtained via the base catalyzed decarbamoylation of 8a-f. The DNA binding affinities for the target dicationic bis-guanidines were assessed by DeltaT(m) values. In vitro antiprotozoal screening of the new compounds showed that derivatives 6a, 9c and 9e possess high to moderate activity against Trypanosoma brucei rhodesiense (T.b.r.) and Plasmodium falciparum (P.f.). While the prodrugs did not yield cures upon oral administration in the antitrypanosomal STIB900 mouse model, compounds 8a and 8c prolonged the survival of the treated mice.
设计用于靶向DNA小沟的一系列三芳基胍和N-取代胍被合成并作为抗原生动物药物进行评估。对这些胍的选定氨基甲酸酯前药进行了口服疗效测定。线性三芳基双胍6a、b由其相应的二胺4a、b通过中间体BOC保护的双胍5a、b制备，然后进行酸催化脱保护。N-取代胍基类似物9c-f通过三步获得，首先使二胺4a、b与异硫氰酸乙酯甲酰酯反应得到氨基甲酰基硫脲7a、b。随后，7a、b在EDCI存在下与各种胺缩合得到氨基甲酰基N-取代胍中间体8a-f，它们也可被视为胍基衍生物的潜在前药。化合物9c-f通过8a-f的碱催化脱氨基甲酰化反应得到。通过ΔT(m)值评估目标双阳离子双胍与DNA的结合亲和力。新化合物的体外抗原生动物筛选表明，衍生物6a、9c和9e对布氏罗得西亚锥虫（T.b.r.）和恶性疟原虫（P.f.）具有高至中等活性。虽然前药在抗锥虫STIB900小鼠模型中口服给药后未能治愈，但化合物8a和8c延长了治疗小鼠的存活时间。
