Ismail Mohamed A, Brun Reto, Wenzler Tanja, Tanious Farial A, Wilson W David, Boykin David W
Department of Chemistry and Center for Biotechnology and Drug Design, Georgia State University, Atlanta, GA 30303-3083, USA
J Med Chem. 2004 Jul 1;47(14):3658-64. doi: 10.1021/jm0400092.
2-[5-(4-Amidinophenyl)-furan-2-yl]-5,6,7,8-tetrahydro-imidazo[1,2-a]pyridine-6-carboxamidine acetate salt (7) was synthesized from 2-[5-(4-cyanophenyl)-furan-2-yl]-imidazo[1,2-a]pyridine-6-carbonitrile (4a), through the bis-O-acetoxyamidoxime followed by hydrogenation in glacial acetic acid. Compound 4a was obtained in four steps starting with two successive brominations of 2-acetylfuran first with N-bromosuccinimide, and second with bromine to form alpha-bromo-2-acetyl-5-bromofuran (2) in a moderate yield. The product (3a), of the condensation reaction between 6-amino-nicotinonitrile and 2, undergoes Suzuki coupling with 4-cyanophenylboronic acid to furnish 4a in good yield. Acetate salt of 2-[5-(4-amidinophenyl)-furan-2-yl]-imidazo[1,2-a]pyridine-6-carboxamidine (8a) was obtained from 4a, through the bis-O-acetoxyamidoxime followed by hydrogenation in a mixture of ethanol/ethyl acetate. N-Methoxy-2-(5-[4-(N-methoxyamidino)-phenyl]-furan-2-yl)-imidazo[1,2-a]pyridine-6-carboxamidine (6) was prepared via methylation of the respective diamidoxime 5a with dimethyl sulfate. By these approaches eight new diamidines and four potential prodrugs were prepared. All of the diamidines showed strong DNA affinities as judged by high DeltaT(m) values. Six of the eight diamidines gave in vitro IC(50) values of 63 nM or less vs T. b. rhodesiense with two exhibiting values of 6 nM and 1 nM. Also, six of the eight diamidines gave in vitro IC(50) values of 88 nM or less vs P. falciparum with two exhibiting values of 14 nM. Excellent in vivo activity in the trypanosomal STIB900 mouse model was found for five of the diamidines on ip dosage; these compounds gave 4/4 cures in this model. The oral activity of the prodrugs was modest with only one showing 2/4 cures in the same mouse model.
2-[5-(4-脒基苯基)-呋喃-2-基]-5,6,7,8-四氢-咪唑并[1,2-a]吡啶-6-甲脒乙酸盐(7)由2-[5-(4-氰基苯基)-呋喃-2-基]-咪唑并[1,2-a]吡啶-6-腈(4a)经双-O-乙酰氧基偕胺肟化，随后在冰醋酸中氢化制得。化合物4a由2-乙酰基呋喃经两步连续溴化反应制得，首先用N-溴代琥珀酰亚胺，然后用溴，以中等产率形成α-溴-2-乙酰基-5-溴呋喃(2)。6-氨基烟腈与产物(3a)发生缩合反应，产物(3a)再与4-氰基苯硼酸进行铃木偶联反应，以良好的产率得到4a。2-[5-(4-脒基苯基)-呋喃-2-基]-咪唑并[1,2-a]吡啶-6-甲脒(8a)的乙酸盐由4a经双-O-乙酰氧基偕胺肟化，随后在乙醇/乙酸乙酯混合溶剂中氢化制得。N-甲氧基-2-(5-[4-(N-甲氧基脒基)-苯基]-呋喃-2-基)-咪唑并[1,2-a]吡啶-6-甲脒(6)通过相应的偕二脒肟5a与硫酸二甲酯甲基化制备。通过这些方法制备了8种新的双脒和4种潜在的前药。通过高ΔT(m)值判断，所有双脒均显示出很强的DNA亲和力。8种双脒中有6种对布氏罗得西亚锥虫的体外IC(50)值为63 nM或更低，其中两种的IC(50)值为6 nM和1 nM。此外，8种双脒中有6种对恶性疟原虫的体外IC(50)值为88 nM或更低，其中两种的IC(50)值为14 nM。在锥虫STIB900小鼠模型中，5种双脒腹腔注射给药显示出优异的体内活性；这些化合物在此模型中实现了4/4治愈。前药的口服活性一般在同一小鼠模型中只有一种显示出2/4治愈。
