Structural properties of dibenzosuberanylpiperazine derivatives for efficient reversal of chloroquine resistance in Plasmodium chabaudi.
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.
School of Pharmaceutical Sciences, Kitasato University, 5-9-1, Shirokane, Minato-ku, Tokyo 108-8641, Japan. osay@pharm.kitasato-u.ac.jp
Yumiko
Y
Osa
Seiki
S
Kobayashi
Yoko
Y
Sato
Yumiko
Y
Suzuki
Kouichi
K
Takino
Tsutomu
T
Takeuchi
Yoshiyuki
Y
Miyata
Masakazu
M
Sakaguchi
Hiroaki
H
Takayanagi
D000818:Animals; D000962:Antimalarials / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D002738:Chloroquine / Q000494:pharmacology*; D018360:Crystallography, X-Ray; D003986:Dibenzocycloheptenes / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D018432:Drug Resistance, Multiple; D005260:Female; D008288:Malaria / Q000188:drug therapy; D051379:Mice; D010879:Piperazines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D016788:Plasmodium chabaudi / Q000187:drug effects*; D013329:Structure-Activity Relationship
D000962:Antimalarials; D003986:Dibenzocycloheptenes; D010879:Piperazines; C474573:dibenzosuberanylpiperazine; D002738:Chloroquine