Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Cairo University, Kasr El-Aini st., 11562, Cairo, Egypt.
Eur J Med Chem. 2011 Dec;46(12):5852-60. doi: 10.1016/j.ejmech.2011.09.047. Epub 2011 Oct 2.
A new series of fourteen dicationic flexible triaryl bis-guanidines 3a,b, bis-N-substituted guanidines 7a,b and 8a,b as well as bis-imidamides 9-12a,b having a 1,3- or 1,4-diphenoxybenzene scaffold backbone were synthesized. The in vitro activity of the novel dications as antiprotozoal agents against Trypanosoma brucei rhodesiense (T.b.r.) and Plasmodium falciparum (P.f.) was assessed. Interestingly, six of the newly synthesized dications viz 3a,b, 7a,b and 8a,b were more active against P.f. than the reference drug pentamidine. Also, some of the dications showed moderate antitrypanosomal activity. Thermal melting analysis of the novel dications was performed to determine their ligand-DNA relative binding affinities. Finally, docking of the dications with an AT rich DNA oligonucleotide was executed to understand their binding mode with the minor groove.
合成了一系列新的十四元双阳离子柔性三芳基双胍 3a,b、双取代胍 7a,b 和 8a,b 以及具有 1,3-或 1,4-二苯氧基苯骨架的双脒 9-12a,b。评估了新型双阳离子作为抗原生动物药物对布氏锥虫罗得西亚亚种（T.b.r.）和恶性疟原虫（P.f.）的体外活性。有趣的是，新合成的六种双阳离子，即 3a,b、7a,b 和 8a,b，对 P.f.的活性均高于参考药物戊脒。此外，一些双阳离子还表现出中等的抗锥虫活性。对新型双阳离子进行热融分析，以确定其配体-DNA 相对结合亲和力。最后，执行双阳离子与富含 AT 的 DNA 寡核苷酸的对接，以了解它们与小沟的结合模式。
