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Dihydroquinazolinone inhibitors of proliferation of blood and liver stage malaria parasites.

Publication ,  Journal Article
Derbyshire, ER; Min, J; Guiguemde, WA; Clark, JA; Connelly, MC; Magalhães, AD; Guy, RK; Clardy, J
Published in: Antimicrobial agents and chemotherapy
January 2014

Drugs that target both the liver and blood stages of malaria will be needed to reduce the disease's substantial worldwide morbidity and mortality. Evaluation of a 259-member library of compounds that block proliferation of the blood stage of malaria revealed several scaffolds--dihydroquinazolinones, phenyldiazenylpyridines, piperazinyl methyl quinolones, and bis-benzimidazoles--with promising activity against the liver stage. Focused structure-activity studies on the dihydroquinazolinone scaffold revealed several molecules with excellent potency against both blood and liver stages. One promising early lead with dual activity is 2-(p-bromophenyl)-3-(2-(diethylamino)ethyl)-2,3-dihydroquinazolin-4(1H)-one with 50% effective concentrations (EC50s) of 0.46 μM and 0.34 μM against liver stage Plasmodium berghei ANKA and blood stage Plasmodium falciparum 3D7 parasites, respectively. Structure-activity relationships revealed that liver stage activity for this compound class requires a 3-dialkyl amino ethyl group and is abolished by substitution at the ortho-position of the phenyl moiety. These compounds have minimal toxicity to mammalian cells and are thus attractive compounds for further development.

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Published In

Antimicrobial agents and chemotherapy

DOI

EISSN

1098-6596

ISSN

0066-4804

Publication Date

January 2014

Volume

58

Issue

3

Start / End Page

1516 / 1522

Related Subject Headings

  • Structure-Activity Relationship
  • Quinazolines
  • Plasmodium falciparum
  • Plasmodium berghei
  • Plasmodium
  • Microbiology
  • Malaria
  • Liver
  • Life Cycle Stages
  • Humans
 

Citation

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Derbyshire, E. R., Min, J., Guiguemde, W. A., Clark, J. A., Connelly, M. C., Magalhães, A. D., … Clardy, J. (2014). Dihydroquinazolinone inhibitors of proliferation of blood and liver stage malaria parasites. Antimicrobial Agents and Chemotherapy, 58(3), 1516–1522. https://doi.org/10.1128/aac.02148-13
Derbyshire, Emily R., Jaeki Min, W Armand Guiguemde, Julie A. Clark, Michele C. Connelly, Andreia D. Magalhães, R Kiplin Guy, and Jon Clardy. “Dihydroquinazolinone inhibitors of proliferation of blood and liver stage malaria parasites.Antimicrobial Agents and Chemotherapy 58, no. 3 (January 2014): 1516–22. https://doi.org/10.1128/aac.02148-13.
Derbyshire ER, Min J, Guiguemde WA, Clark JA, Connelly MC, Magalhães AD, et al. Dihydroquinazolinone inhibitors of proliferation of blood and liver stage malaria parasites. Antimicrobial agents and chemotherapy. 2014 Jan;58(3):1516–22.
Derbyshire, Emily R., et al. “Dihydroquinazolinone inhibitors of proliferation of blood and liver stage malaria parasites.Antimicrobial Agents and Chemotherapy, vol. 58, no. 3, Jan. 2014, pp. 1516–22. Epmc, doi:10.1128/aac.02148-13.
Derbyshire ER, Min J, Guiguemde WA, Clark JA, Connelly MC, Magalhães AD, Guy RK, Clardy J. Dihydroquinazolinone inhibitors of proliferation of blood and liver stage malaria parasites. Antimicrobial agents and chemotherapy. 2014 Jan;58(3):1516–1522.

Published In

Antimicrobial agents and chemotherapy

DOI

EISSN

1098-6596

ISSN

0066-4804

Publication Date

January 2014

Volume

58

Issue

3

Start / End Page

1516 / 1522

Related Subject Headings

  • Structure-Activity Relationship
  • Quinazolines
  • Plasmodium falciparum
  • Plasmodium berghei
  • Plasmodium
  • Microbiology
  • Malaria
  • Liver
  • Life Cycle Stages
  • Humans