Structural properties of dibenzosuberanylpiperazine derivatives for efficient reversal of chloroquine resistance in Plasmodium chabaudi

Yumiko Osa, Seiki Kobayashi, Yoko Sato, Yumiko Suzuki, Kouichi Takino, Tsutomu Takeuchi, Yoshiyuki Miyata, Masakazu Sakaguchi, Hiroaki Takayanagi

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Abstract

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.

Original languageEnglish
Pages (from-to)1948-1956
Number of pages9
JournalJournal of Medicinal Chemistry
Volume46
Issue number10
DOIs
Publication statusPublished - 2003 May 8

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Plasmodium chabaudi
Chloroquine
Antimalarials
Structural properties
Chlorides
Derivatives
Epoxy Compounds
Bioactivity
Malaria
Amines
Infection
Pharmaceutical Preparations
piperazine
dibenzosuberanylpiperazine

ASJC Scopus subject areas

  • Organic Chemistry

Cite this

Structural properties of dibenzosuberanylpiperazine derivatives for efficient reversal of chloroquine resistance in Plasmodium chabaudi. / Osa, Yumiko; Kobayashi, Seiki; Sato, Yoko; Suzuki, Yumiko; Takino, Kouichi; Takeuchi, Tsutomu; Miyata, Yoshiyuki; Sakaguchi, Masakazu; Takayanagi, Hiroaki.

In: Journal of Medicinal Chemistry, Vol. 46, No. 10, 08.05.2003, p. 1948-1956.

Research output: Contribution to journalArticle

Osa, Y, Kobayashi, S, Sato, Y, Suzuki, Y, Takino, K, Takeuchi, T, Miyata, Y, Sakaguchi, M & Takayanagi, H 2003, 'Structural properties of dibenzosuberanylpiperazine derivatives for efficient reversal of chloroquine resistance in Plasmodium chabaudi', Journal of Medicinal Chemistry, vol. 46, no. 10, pp. 1948-1956. https://doi.org/10.1021/jm020379v
Osa, Yumiko ; Kobayashi, Seiki ; Sato, Yoko ; Suzuki, Yumiko ; Takino, Kouichi ; Takeuchi, Tsutomu ; Miyata, Yoshiyuki ; Sakaguchi, Masakazu ; Takayanagi, Hiroaki. / Structural properties of dibenzosuberanylpiperazine derivatives for efficient reversal of chloroquine resistance in Plasmodium chabaudi. In: Journal of Medicinal Chemistry. 2003 ; Vol. 46, No. 10. pp. 1948-1956.
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abstract = "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.",
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AU - Osa, Yumiko

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AU - Sato, Yoko

AU - Suzuki, Yumiko

AU - Takino, Kouichi

AU - Takeuchi, Tsutomu

AU - Miyata, Yoshiyuki

AU - Sakaguchi, Masakazu

AU - Takayanagi, Hiroaki

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