Synthesis and antiprotozoal activity of novel bis-benzamidino imidazo[1,2-a]pyridines and 5,6,7,8-tetrahydroimidazo[1,2-a]pyridines
Synthesis and antiprotozoal activity of novel bis-benzamidino imidazo[1,2-a]pyridines and 5,6,7,8-tetrahydroimidazo[1,2-a]pyridines
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DOI：
10.1016/j.bmc.2007.10.042
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发表时间：
2008-01-15
影响因子：
3.5
通讯作者：
Boykin, David W.
中科院分区：
文献类型：
--
作者：
Ismail, Mohamed A.;Arafa, Reem K.;Boykin, David W.
通过苯甲酰溴 1 与适当的 2-氨基-5-溴吡啶反应生成 3a-d，合成了关键的二腈中间体 4a-d。 3a-d与4-氰基苯基硼酸的Suzuki偶联产生2,6-双(4-氰基苯基)-咪唑并[1,2-a]吡啶衍生物4a-d。通过羟胺的作用由4a-d获得的双-偕胺肟5a-d被转化为双-O-乙酰氧基偕胺肟，其在乙醇/乙酸乙酯的混合物中催化氢化得到乙酸盐或2,6-双[4-(脒基苯基)]-咪唑并[1,2-a]吡啶7a-d。 5a的双-O-乙酰氧基偕胺肟在冰醋酸中得到饱和类似物2,6-双[4-(脒基苯基)]-5,6,7,8-四氢-咪唑并[1,2-a]吡啶8。偕胺肟5a-d的0-甲基化得到N-甲氧基脒6a-d。二脒显示出很强的 DNA 结合亲和力，在体外对 T. b. 非常有效。河表现出 7 至 38 nM 之间的 IC50 值，但对 P. f 的效果较差，IC50 值在 23 至 92 nM 之间。在 T b 中，二脒 7c 和 7d 中的两个比呋喃西啶的活性稍高，但比氮杂呋喃啶的活性低。河STIB900 鼠标型号。在同一小鼠模型中，只有一种前药 6b 显示出中等活性。 (c) 2007 Elsevier Ltd. 保留所有权利。
The key dinitrile intermediates 4a-d were synthesized by reaction of phenacyl bromide 1 and the appropriate 2-amino-5-bromopyridines to yield 3a-d. Suzuki coupling of 3a-d with 4-cyanophenylboronic acid yielded the 2,6-bis(4-cyanophenyl)-imidazo[1,2-a]pyridine derivatives 4a-d. The bis-amidoximes 5a-d, obtained from 4a-d by the action of hydroxylamine, were converted to the bis-O-acetoxyamidoximes which on catalytic hydrogenation in a mixture of ethanol/ethyl acetate gave the acetate salts or 2,6-bis[4-(amidinophenyl)]-imidazo[1,2-a]pyridines 7a-d, In contrast, catalytic hydrogenation of the bis-O-acetoxyamidoxime of 5a in glacial acetic acid gave the saturated analogue 2,6-bis[4-(amidinophenyl)]-5,6,7,8-tetrahydro-imidazo[1,2-a]pyridine8. 0-Methylation of the amidoximes 5a-d gave the N-methoxyamidines 6a-d. The diamidines showed strong DNA binding affinity, were very active in vitro against T. b. r. exhibiting IC50 values between 7 and 38 nM, but were less effective against P. f with IC50 values between 23 and 92 nM. Two of the diamidines 7c and 7d were slightly more active than furamidine but less active than azafuramidine in the T b. r. STIB900 mouse model. Only one prodrug 6b showed moderate activity in the same mouse model. (c) 2007 Elsevier Ltd. All rights reserved.