N10,N11-di-alkylamine indolo[3,2-b]quinolines as hemozoin inhibitors: design, synthesis and antiplasmodial activity

Marta Figueiras; Lis Coelho; Kathryn J. Wicht; Sofia A. Santos; João Lavrado; Jiri Gut; Philip J. Rosenthal; Fátima Nogueira; Timothy J. Egan; Rui Moreira; Alexandra Paulo

doi:10.1016/j.bmc.2015.02.007

N10,N11-di-alkylamine indolo[3,2-b]quinolines as hemozoin inhibitors: design, synthesis and antiplasmodial activity

Marta Figueiras, Lis Coelho, Kathryn J. Wicht, Sofia A. Santos, João Lavrado, Jiri Gut, Philip J. Rosenthal, Fátima Nogueira, Timothy J. Egan, Rui Moreira, Alexandra Paulo^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

19 Citations (Scopus)

Abstract

We recently reported that potent N10,O11-bis-alkylamine indolo[3,2-b]quinoline antimalarials act as hemozoin (Hz) growth inhibitors. To improve access and binding to the target we have now designed novel N10,N11-di-alkylamine bioisosteres. 3-Chloro derivatives (10a-f) showed selectivity for malaria parasite compared to human cells, high activity against Plasmodium falciparum chloroquine (CQ)-resistant strain W2 (IC₅₀s between 20 and 158 nM), good correlation with β-hematin inhibition and improved vacuolar accumulation ratios, thus suggesting inhibition of Hz growth as one possible mechanism of action for these compounds. Moreover, our studies show that Hz is a valid target for the development of new antimalarials able to overcome CQ resistance.

Original language	English
Pages (from-to)	1530-1539
Number of pages	10
Journal	Bioorganic and Medicinal Chemistry
Volume	23
Issue number	7
DOIs	https://doi.org/10.1016/j.bmc.2015.02.007
Publication status	Published - 1 Apr 2015
Externally published	Yes

Keywords

Hemozoin
Indolo[3 2-b]quinolines
Malaria
Resistance
Vacuolar accumulation

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.bmc.2015.02.007

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title = "N10,N11-di-alkylamine indolo[3,2-b]quinolines as hemozoin inhibitors: design, synthesis and antiplasmodial activity",

abstract = "We recently reported that potent N10,O11-bis-alkylamine indolo[3,2-b]quinoline antimalarials act as hemozoin (Hz) growth inhibitors. To improve access and binding to the target we have now designed novel N10,N11-di-alkylamine bioisosteres. 3-Chloro derivatives (10a-f) showed selectivity for malaria parasite compared to human cells, high activity against Plasmodium falciparum chloroquine (CQ)-resistant strain W2 (IC50s between 20 and 158 nM), good correlation with β-hematin inhibition and improved vacuolar accumulation ratios, thus suggesting inhibition of Hz growth as one possible mechanism of action for these compounds. Moreover, our studies show that Hz is a valid target for the development of new antimalarials able to overcome CQ resistance.",

keywords = "Hemozoin, Indolo[3 2-b]quinolines, Malaria, Resistance, Vacuolar accumulation",

author = "Marta Figueiras and Lis Coelho and Wicht, {Kathryn J.} and Santos, {Sofia A.} and Jo{\~a}o Lavrado and Jiri Gut and Rosenthal, {Philip J.} and F{\'a}tima Nogueira and Egan, {Timothy J.} and Rui Moreira and Alexandra Paulo",

year = "2015",

month = apr,

day = "1",

doi = "10.1016/j.bmc.2015.02.007",

language = "English",

volume = "23",

pages = "1530--1539",

journal = "Bioorganic and Medicinal Chemistry",

issn = "0968-0896",

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}

TY - JOUR

T1 - N10,N11-di-alkylamine indolo[3,2-b]quinolines as hemozoin inhibitors

T2 - design, synthesis and antiplasmodial activity

AU - Figueiras, Marta

AU - Coelho, Lis

AU - Wicht, Kathryn J.

AU - Santos, Sofia A.

AU - Lavrado, João

AU - Gut, Jiri

AU - Rosenthal, Philip J.

AU - Nogueira, Fátima

AU - Egan, Timothy J.

AU - Moreira, Rui

AU - Paulo, Alexandra

PY - 2015/4/1

Y1 - 2015/4/1

N2 - We recently reported that potent N10,O11-bis-alkylamine indolo[3,2-b]quinoline antimalarials act as hemozoin (Hz) growth inhibitors. To improve access and binding to the target we have now designed novel N10,N11-di-alkylamine bioisosteres. 3-Chloro derivatives (10a-f) showed selectivity for malaria parasite compared to human cells, high activity against Plasmodium falciparum chloroquine (CQ)-resistant strain W2 (IC50s between 20 and 158 nM), good correlation with β-hematin inhibition and improved vacuolar accumulation ratios, thus suggesting inhibition of Hz growth as one possible mechanism of action for these compounds. Moreover, our studies show that Hz is a valid target for the development of new antimalarials able to overcome CQ resistance.

AB - We recently reported that potent N10,O11-bis-alkylamine indolo[3,2-b]quinoline antimalarials act as hemozoin (Hz) growth inhibitors. To improve access and binding to the target we have now designed novel N10,N11-di-alkylamine bioisosteres. 3-Chloro derivatives (10a-f) showed selectivity for malaria parasite compared to human cells, high activity against Plasmodium falciparum chloroquine (CQ)-resistant strain W2 (IC50s between 20 and 158 nM), good correlation with β-hematin inhibition and improved vacuolar accumulation ratios, thus suggesting inhibition of Hz growth as one possible mechanism of action for these compounds. Moreover, our studies show that Hz is a valid target for the development of new antimalarials able to overcome CQ resistance.

KW - Hemozoin

KW - Indolo[3 2-b]quinolines

KW - Malaria

KW - Resistance

KW - Vacuolar accumulation

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U2 - 10.1016/j.bmc.2015.02.007

DO - 10.1016/j.bmc.2015.02.007

M3 - Article

C2 - 25725608

SN - 0968-0896

VL - 23

SP - 1530

EP - 1539

JO - Bioorganic and Medicinal Chemistry

JF - Bioorganic and Medicinal Chemistry

IS - 7

ER -

N10,N11-di-alkylamine indolo[3,2-b]quinolines as hemozoin inhibitors: design, synthesis and antiplasmodial activity

Abstract

Keywords

UN SDGs

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