Department of Pharmaceutical Chemistry, Faculty of Pharmacy and Biotechnology, German University in Cairo, Egypt.
Med Chem. 2010 Nov;6(6):374-87. doi: 10.2174/157340610793563992.
Starting from a previously reported lead compound GR30040X (a hydantoin tetrahydro-β-carboline derivative with a 4- pyridinyl ring at C- 5), a series of structurally related tetrahydro-β-carboline derivatives were prepared. The tetrahydro-β-carboline skeleton was fused either to a hydantoin or to a piperazindione ring, the pendant aryl group attached to C-5 or C-6 was changed to a 3, 4-dimethoxyphenyl or a 3-pyridinyl ring; different N-substituents on the terminal ring were introduced, a straight chain ethyl group, a branched tert. butyl and P-chlorophenyl group rather than n-butyl group of the lead compound. All four possible diastereomers of target tetrahydro-β-carboline derivatives were prepared, separated by column chromatography and the significance of these stereochemical manipulations were studied. Synthesized compounds were evaluated for their inhibitory effect versus PDE5. Seven hits were obtained with appreciable inhibitory activity versus PDE5 with IC₅₀s 0.14 - 4.99 µM.
从先前报道的先导化合物 GR30040X（一种 5-位带有 4-吡啶基环的海因四氢-β-咔啉衍生物）出发，合成了一系列结构相关的四氢-β-咔啉衍生物。四氢-β-咔啉骨架与海因或哌嗪二酮环融合，连接在 C-5 或 C-6 上的芳基取代基被改为 3,4-二甲氧基苯基或 3-吡啶基环；末端环上引入了不同的 N-取代基，取代基为直链乙基、支链叔丁基和对氯苯基，而不是先导化合物的正丁基。目标四氢-β-咔啉衍生物的四个可能的非对映异构体均已合成，通过柱层析分离，并研究了这些立体化学操作的意义。合成的化合物被评估了对 PDE5 的抑制作用。其中 7 个化合物对 PDE5 具有显著的抑制活性，IC₅₀ 值为 0.14-4.99 μM。
