Anticonvulsants containing the N-(3-aryl-2-propenoyl) amido pharmacophore
Anticonvulsants containing the N-(3-aryl-2-propenoyl) amido pharmacophore
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DOI：
10.1080/14756360409162442
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发表时间：
2004-08-01
影响因子：
5.6
通讯作者：
Santos, CL
中科院分区：
文献类型：
--
作者：
Dimmock, JR;Gunda, SGR;Santos, CL
合成了一系列1-(3-芳基-2-丙烯酰基)-4-氧基哌啶(1)及其相关的氨基脲(2)和缩氨基硫脲(3)，以确定芳环和酰胺基团的相对位置是否会导致新的抗惊厥药物。最初，这些化合物被注射到小鼠的腹膜内，并在最大电休克(MES)、皮下戊四氮(ScPTZ)和神经毒性(NT)筛查中进行检测。生物数据显示，系列(1)中的大部分化合物都具有抗惊厥作用，而系列(3)中的一半化合物(2)没有保护作用。利用分子模拟来比较系列(1-3)中具有代表性的化合物中苯环相对于酰胺基团的位置与先前报道的抗惊厥剂。4-氧代-1-(3-苯基-2-丙烯酰基)哌啶(1a)的分子简化得到了1-(3-苯基-2-丙烯酰基)哌啶(7)和N，N-二乙基肉桂酰胺(8)，并保留了抗惊厥的性质。(1a)和(8)在大鼠海马区点燃屏幕上均有保护作用。当给大鼠口服时，(1a)和(8)在MES屏幕上显示出活性，在(8)的情况下，观察到巨大的保护指数，表明它是一种重要的先导化合物。所有化合物对小鼠P388细胞的IC_(50)值均大于50微米，其中几个化合物对结核分枝杆菌具有细胞毒性。
A series of 1-(3-aryl-2-propenoyl)-4-oxopiperidines (1) as well as some related semicarbazones (2) and thiosemicarbazones (3) were prepared in order to determine whether the relative locations of aryl rings and amidic groups would lead to novel anticonvulsant agents. Initially the compounds were administered intraperitoneally to mice and examined in the maximal electroshock (MES), subcutaneous pentylenetetrazole (scPTZ) and neurotoxicity (NT) screens. The biodata revealed that anticonvulsant properties were displayed by most of the compounds in series (1), in half of the semicarbazones (2) while protection was absent by members of series (3). Molecular modeling was utilized in order to compare the positions of a phenyl ring in relation to amidic groups in representative compounds in series (1-3) with previously reported anticonvulsant agents. Molecular simplification of 4-oxo-1-(3-phenyl-2-propenoyl)piperidine (1a) led to 1-(3-phenyl-2-propenoyl)piperidine (7) and N,N-diethylcinnamamide (8) with retention of anticonvulsant properties. Both (1a) and (8) afforded protection in the hippocampal kindling screen in rats. When administered orally to rats, (1a) and (8) demonstrated activity in the MES screen and in the case of (8), a huge protection index was observed revealing it to be an important lead compound. The IC50 values of all of the compounds towards murine P388 cells were in excess of 50 muM while several compounds displayed cytotoxicity towards Mycobacterium tuberculosis.