Osa Yumiko, Kobayashi Seiki, Sato Yoko, Suzuki Yumiko, Takino Kouichi, Takeuchi Tsutomu, Miyata Yoshiyuki, Sakaguchi Masakazu, Takayanagi Hiroaki
School of Pharmaceutical Sciences, Kitasato University, 5-9-1, Shirokane, Minato-ku, Tokyo 108-8641, Japan.
J Med Chem. 2003 May 8;46(10):1948-56. doi: 10.1021/jm020379v.
For the purpose of developing chemosensitizers to reverse chloroquine (CQ) resistance in Plasmodium chabaudi in vivo, dibenzosuberanylpiperazine (1-(10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-yl)piperazine) (DSP) and its piperazin-1-yl derivatives were synthesized systematically. DSP hydrochloride (3) was obtained from the reaction of dibenzosuberanyl chloride with piperazine in the presence of 1,8-diazabicyclo[5,4,0]-7-undecene (DBU). To understand the relationship between the substituent patterns of DSP derivatives and their biological activities, 13 hydroxyalkyl or hydroxyalkenyl derivatives were synthesized by an attack of the piperazine secondary amine of 3 on commercially available epoxides in the presence of triethylamine or DBU, and three alkyl or alkynyl derivatives were synthesized by the reactions of 3 with the corresponding organic chlorides in the presence of DBU. In both reactions, the yield was a maximum of 90%. The biological activities of the synthesized compounds were evaluated on the basis of two values: antimalarial activity and reversal activity. The values of antimalarial activities by single administration of 17 test compounds were not effective, being in the range 67-152% on day 4 after infection of Plasmodium chabaudi to mice except for the administration of 3-(dibenzosuberanylpiperazin-1-yl)-1-butene (29, 22%). On the other hand, administration of the seven test compounds (50 mg/kg dose) combined with CQ (3-4 mg/kg) gave high reversal activities, namely, low values (0% on day 4). The effective test compounds were those obtained by introducing the following substituents: 2-hydroxybutyl (24), 2-hydroxyhexen-5-yl (27), 2-hydroxybuten-3-yl (28a), 2-substituted 1-hydroxybuten-3-yl (28b), 4-acetoxybutyn-2-yl (30), 4-hydroxybutyn-2-yl (31), and 3-substituted buten-1-yl (29), which correspond to the nonbulky groups of hydroxyalkyl (C4), hydroxyalkenyl (C4-C6), hydroxyalkynyl (C4), or alkenyl (C4). These results may lead to the development of an approach to developing clinically applicable chemosensitizers for drug-resistant malaria.
为了开发化学增敏剂以在体内逆转查巴迪疟原虫对氯喹（CQ）的抗性，系统地合成了二苯并环庚烯基哌嗪（1-(10,11-二氢-5H-二苯并[a,d]环庚烯-5-基)哌嗪）（DSP）及其哌嗪-1-基衍生物。DSP盐酸盐（3）是由二苯并环庚烯基氯与哌嗪在1,8-二氮杂双环[5,4,0]-7-十一碳烯（DBU）存在下反应制得的。为了了解DSP衍生物的取代基模式与其生物活性之间的关系，在三乙胺或DBU存在下，通过3的哌嗪仲胺对市售环氧化合物的进攻合成了13种羟烷基或羟烯基衍生物，并在DBU存在下通过3与相应有机氯反应合成了3种烷基或炔基衍生物。在这两种反应中，产率最高为90%。根据两个值评估合成化合物的生物活性：抗疟活性和逆转活性。单次给予17种测试化合物的抗疟活性值无效，在感染查巴迪疟原虫的小鼠感染后第4天，除了给予3-(二苯并环庚烯基哌嗪-1-基)-1-丁烯（29，22%）外，活性范围为67 - 152%。另一方面，将7种测试化合物（50 mg/kg剂量）与CQ（3 - 4 mg/kg）联合给药具有高逆转活性，即低数值（第4天为0%）。有效的测试化合物是通过引入以下取代基获得的：2-羟丁基（24）、2-羟己烯-5-基（27）、2-羟丁烯-3-基（28a）、2-取代的1-羟丁烯-3-基（28b）、4-乙酰氧基丁炔-2-基（30）、4-羟丁炔-2-基（31）和3-取代的丁烯-1-基（29），它们对应于羟烷基（C4）、羟烯基（C4 - C6）、羟炔基（C4）或烯基（C4）的非庞大基团。这些结果可能会导致开发一种针对耐药疟疾开发临床适用化学增敏剂的方法。
