Extended aromatic furan amidino derivatives as anti-Pneumocystis carinii agents
Extended aromatic furan amidino derivatives as anti-Pneumocystis carinii agents
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DOI：
10.1021/jm980230c
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发表时间：
1998-09-24
影响因子：
7.3
通讯作者：
Boykin, DW
中科院分区：
文献类型：
--
作者：
Hopkins, KT;Wilson, WD;Boykin, DW
的.本文报道了9种新的含扩链芳环的2，5-双[4-（N-烷基脒基）苯基]呋喃衍生物的合成。通过T（m）测量确定这些双阳离子呋喃与poly（dA）*poly（dT）以及与双链体寡聚体d（CGCGAATTCGCG）（2）和d（GCGAATTCGC）（2）的相互作用，并评价这些化合物对免疫抑制的卡氏肺孢子虫大鼠模型的有效性。在10 μ mol/kg的筛选剂量下，本文描述的12种脒基呋喃中的4种比母体化合物1更有活性。一般来说，在不存在脒基氮取代的情况下，芳香体系的延伸导致对DNA的亲和力高于母体化合物，这是通过较大的Δ T（m）值来判断的，并表明脒基呋喃-DNA复合物中的货车德瓦尔斯相互作用增强。当以10 μ mol/kg的剂量施用时，化合物3、5和11中的三种产生小于对照的0.1%的孢囊计数。化合物3不具有延伸的芳族系统，是最具活性的衍生物。虽然没有观察到抗卡氏肺孢子虫活性和DNA结合亲和力之间的直接相关性，但所有具有显著活性的化合物都具有大的Δ T（m）值。
The. syntheses of nine new derivatives of 2,5-bis[4-(N-alkylamidino)phenyl]furans with extended aromatic systems are reported. The interaction of these dicationic furans with poly(dA)*poly(dT) and with the duplex oligomers d(CGCGAATTCGCG)(2) and d(GCGAATTCGC)(2) was determined by T(m) measurement, and the effectiveness of these compounds against the immunosuppressed rat model of Pneumocystis carinii was evaluated. At a screening dose of 10 mu mol/kg, 4 of the 12 amidino furans described here are more active than the parent compound 1. In general, extension of the aromatic system in the absence of a substitution of the amidino nitrogens resulted in higher affinity for DNA than the parent compound as judged by the larger Delta T(m) values and suggests enhanced van der Waals interactions in the amidino furan-DNA complex. Three of the compounds, 3, 5, and 11, yield cysts counts of less than 0.1% of control when administered at a dosage of 10 mu mol/kg. Compound 3, which does not have an extended aromatic system, is the most active derivative. Although a direct correlation between anti-P. carinii activity and DNA binding affinity was not observed, all compounds which have significant activity have large Delta T(m) values.