Bisquinolines. 1. N,N-bis(7-chloroquinolin-4-yl)alkanediamines with potential against chloroquine-resistant malaria

Jonathan L. Vennerstrom, William Y. Ellis, Arba L Ager, Steven L. Andersen, Lucia Gerena, Wilbur K. Milhous

Research output: Contribution to journalArticle

113 Citations (Scopus)

Abstract

On the basis of observations that several bisquinolines such as piperaquine possess notable activity against chloroquine-resistant malaria, 13 N,N-bis-(7-chloroquinolin-4-yl)alkanediamines were synthesized and screened against Plasmodium falciparum in vitro and Plasmodium berghei in vivo. Twelve of the thirteen bisquinolines had a significantly lower resistance index than did chloroquine; the resistance index was apparently unrelated to either in vitro or in vivo activity. Except for two compounds, there was a reasonable correlation between in vitro and in vivo activities. Seven of the thirteen bisquinolines had IC50's of less than 6 nM against both chloroquine-sensitive (D-6) and -resistant (W-2) clones of P. falciparum and were curative against P. berghei at doses of 640 mg/kg. In contrast to chloroquine, these bisquinolines did not show any toxic deaths at curative dose levels. Four bisquinolines, however, caused skin lesions at the site of injection. Maximum activity was seen in bisquinolines with a connecting bridge of two carbon atoms where decreased conformational mobility seemed to increase activity. Bisquinoline 3 ((±)-trans-N1,N 2-bis(7-chloroquinolin-4-yl)cyclohexane-1,2-diamine was not only the most potent bisquinoline in vitro, but was clearly unique in its in vivo activity - 80% and 100% cure rates were achieved at doses of 160 and 320 mg/kg, respectively. In summary, these preliminary results support the premise that bisquinolines may be useful agents against chloroquine-resistant malaria.

Original languageEnglish (US)
Pages (from-to)2129-2134
Number of pages6
JournalJournal of Medicinal Chemistry
Volume35
Issue number11
StatePublished - 1992

Fingerprint

Chloroquine
Malaria
Plasmodium berghei
Plasmodium falciparum
Poisons
Inhibitory Concentration 50
Skin
Carbon
Clone Cells
Atoms
Injections
In Vitro Techniques

ASJC Scopus subject areas

  • Organic Chemistry

Cite this

Vennerstrom, J. L., Ellis, W. Y., Ager, A. L., Andersen, S. L., Gerena, L., & Milhous, W. K. (1992). Bisquinolines. 1. N,N-bis(7-chloroquinolin-4-yl)alkanediamines with potential against chloroquine-resistant malaria. Journal of Medicinal Chemistry, 35(11), 2129-2134.

Bisquinolines. 1. N,N-bis(7-chloroquinolin-4-yl)alkanediamines with potential against chloroquine-resistant malaria. / Vennerstrom, Jonathan L.; Ellis, William Y.; Ager, Arba L; Andersen, Steven L.; Gerena, Lucia; Milhous, Wilbur K.

In: Journal of Medicinal Chemistry, Vol. 35, No. 11, 1992, p. 2129-2134.

Research output: Contribution to journalArticle

Vennerstrom, JL, Ellis, WY, Ager, AL, Andersen, SL, Gerena, L & Milhous, WK 1992, 'Bisquinolines. 1. N,N-bis(7-chloroquinolin-4-yl)alkanediamines with potential against chloroquine-resistant malaria', Journal of Medicinal Chemistry, vol. 35, no. 11, pp. 2129-2134.
Vennerstrom, Jonathan L. ; Ellis, William Y. ; Ager, Arba L ; Andersen, Steven L. ; Gerena, Lucia ; Milhous, Wilbur K. / Bisquinolines. 1. N,N-bis(7-chloroquinolin-4-yl)alkanediamines with potential against chloroquine-resistant malaria. In: Journal of Medicinal Chemistry. 1992 ; Vol. 35, No. 11. pp. 2129-2134.
@article{cf561c408f654d0f89f58d2e437bc026,
title = "Bisquinolines. 1. N,N-bis(7-chloroquinolin-4-yl)alkanediamines with potential against chloroquine-resistant malaria",
abstract = "On the basis of observations that several bisquinolines such as piperaquine possess notable activity against chloroquine-resistant malaria, 13 N,N-bis-(7-chloroquinolin-4-yl)alkanediamines were synthesized and screened against Plasmodium falciparum in vitro and Plasmodium berghei in vivo. Twelve of the thirteen bisquinolines had a significantly lower resistance index than did chloroquine; the resistance index was apparently unrelated to either in vitro or in vivo activity. Except for two compounds, there was a reasonable correlation between in vitro and in vivo activities. Seven of the thirteen bisquinolines had IC50's of less than 6 nM against both chloroquine-sensitive (D-6) and -resistant (W-2) clones of P. falciparum and were curative against P. berghei at doses of 640 mg/kg. In contrast to chloroquine, these bisquinolines did not show any toxic deaths at curative dose levels. Four bisquinolines, however, caused skin lesions at the site of injection. Maximum activity was seen in bisquinolines with a connecting bridge of two carbon atoms where decreased conformational mobility seemed to increase activity. Bisquinoline 3 ((±)-trans-N1,N 2-bis(7-chloroquinolin-4-yl)cyclohexane-1,2-diamine was not only the most potent bisquinoline in vitro, but was clearly unique in its in vivo activity - 80{\%} and 100{\%} cure rates were achieved at doses of 160 and 320 mg/kg, respectively. In summary, these preliminary results support the premise that bisquinolines may be useful agents against chloroquine-resistant malaria.",
author = "Vennerstrom, {Jonathan L.} and Ellis, {William Y.} and Ager, {Arba L} and Andersen, {Steven L.} and Lucia Gerena and Milhous, {Wilbur K.}",
year = "1992",
language = "English (US)",
volume = "35",
pages = "2129--2134",
journal = "Journal of Medicinal Chemistry",
issn = "0022-2623",
publisher = "American Chemical Society",
number = "11",

}

TY - JOUR

T1 - Bisquinolines. 1. N,N-bis(7-chloroquinolin-4-yl)alkanediamines with potential against chloroquine-resistant malaria

AU - Vennerstrom, Jonathan L.

AU - Ellis, William Y.

AU - Ager, Arba L

AU - Andersen, Steven L.

AU - Gerena, Lucia

AU - Milhous, Wilbur K.

PY - 1992

Y1 - 1992

N2 - On the basis of observations that several bisquinolines such as piperaquine possess notable activity against chloroquine-resistant malaria, 13 N,N-bis-(7-chloroquinolin-4-yl)alkanediamines were synthesized and screened against Plasmodium falciparum in vitro and Plasmodium berghei in vivo. Twelve of the thirteen bisquinolines had a significantly lower resistance index than did chloroquine; the resistance index was apparently unrelated to either in vitro or in vivo activity. Except for two compounds, there was a reasonable correlation between in vitro and in vivo activities. Seven of the thirteen bisquinolines had IC50's of less than 6 nM against both chloroquine-sensitive (D-6) and -resistant (W-2) clones of P. falciparum and were curative against P. berghei at doses of 640 mg/kg. In contrast to chloroquine, these bisquinolines did not show any toxic deaths at curative dose levels. Four bisquinolines, however, caused skin lesions at the site of injection. Maximum activity was seen in bisquinolines with a connecting bridge of two carbon atoms where decreased conformational mobility seemed to increase activity. Bisquinoline 3 ((±)-trans-N1,N 2-bis(7-chloroquinolin-4-yl)cyclohexane-1,2-diamine was not only the most potent bisquinoline in vitro, but was clearly unique in its in vivo activity - 80% and 100% cure rates were achieved at doses of 160 and 320 mg/kg, respectively. In summary, these preliminary results support the premise that bisquinolines may be useful agents against chloroquine-resistant malaria.

AB - On the basis of observations that several bisquinolines such as piperaquine possess notable activity against chloroquine-resistant malaria, 13 N,N-bis-(7-chloroquinolin-4-yl)alkanediamines were synthesized and screened against Plasmodium falciparum in vitro and Plasmodium berghei in vivo. Twelve of the thirteen bisquinolines had a significantly lower resistance index than did chloroquine; the resistance index was apparently unrelated to either in vitro or in vivo activity. Except for two compounds, there was a reasonable correlation between in vitro and in vivo activities. Seven of the thirteen bisquinolines had IC50's of less than 6 nM against both chloroquine-sensitive (D-6) and -resistant (W-2) clones of P. falciparum and were curative against P. berghei at doses of 640 mg/kg. In contrast to chloroquine, these bisquinolines did not show any toxic deaths at curative dose levels. Four bisquinolines, however, caused skin lesions at the site of injection. Maximum activity was seen in bisquinolines with a connecting bridge of two carbon atoms where decreased conformational mobility seemed to increase activity. Bisquinoline 3 ((±)-trans-N1,N 2-bis(7-chloroquinolin-4-yl)cyclohexane-1,2-diamine was not only the most potent bisquinoline in vitro, but was clearly unique in its in vivo activity - 80% and 100% cure rates were achieved at doses of 160 and 320 mg/kg, respectively. In summary, these preliminary results support the premise that bisquinolines may be useful agents against chloroquine-resistant malaria.

UR - http://www.scopus.com/inward/record.url?scp=0026762480&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0026762480&partnerID=8YFLogxK

M3 - Article

C2 - 1597862

AN - SCOPUS:0026762480

VL - 35

SP - 2129

EP - 2134

JO - Journal of Medicinal Chemistry

JF - Journal of Medicinal Chemistry

SN - 0022-2623

IS - 11

ER -