volume 54 issue 13 pages 4581-4589

Antimalarial Pyrido[1,2-a]benzimidazoles

Albert J Ndakala 1
Richard K Gessner 2
Patricia W. Gitari 2
Natasha October 2
KAREN E. WHITE 3
Alan Hudson 4
Foluke Fakorede 5
D. Shackleford 3
Clive Yeates 7
Susan C Charman 3
Kelly Chibale 2
Publication typeJournal Article
Publication date2011-06-16
scimago Q1
wos Q1
SJR1.801
CiteScore11.5
Impact factor6.8
ISSN00222623, 15204804
PubMed ID:  21644541
Drug Discovery
Molecular Medicine
Abstract
A novel class of antimalarial pyrido[1,2-a]benzimidazoles were synthesized and evaluated for antiplasmodial activity and cytotoxicity following hits identified from screening commercially available compound collections. The most active of these, TDR86919 (4c), showed improved in vitro activity vs the drug-resistant K1 strain of Plasmodium falciparum relative to chloroquine (IC(50) = 0.047 μM v 0.17 μM); potency was retained against a range of drug-sensitive and drug-resistant strains, with negligible cytotoxicity against the mammalian (L-6) cell line (selectivity index of >600). 4c and several close analogues (as HCl or mesylate salts) showed significant efficacy in P. berghei infected mice following both intraperitoneal (ip) and oral (po) administration, with >90% inhibition of parasitemia, accompanied by an increase in the mean survival time (MSD). The pyrido[1,2-a]benzimidazoles appeared to be relatively slow acting in vivo compared to chloroquine, and metabolic stability of the alkylamino side chain was identified as a key issue in influencing in vivo activity.
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GOST |
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GOST Copy
Ndakala A. J. et al. Antimalarial Pyrido[1,2-a]benzimidazoles // Journal of Medicinal Chemistry. 2011. Vol. 54. No. 13. pp. 4581-4589.
GOST all authors (up to 50) Copy
Ndakala A. J., Gessner R. K., Gitari P. W., October N., WHITE K. E., Hudson A., Fakorede F., Shackleford D., Kaiser M., Yeates C., Charman S. C., Chibale K. Antimalarial Pyrido[1,2-a]benzimidazoles // Journal of Medicinal Chemistry. 2011. Vol. 54. No. 13. pp. 4581-4589.
RIS |
Cite this
RIS Copy
TY - JOUR
DO - 10.1021/jm200227r
UR - https://doi.org/10.1021/jm200227r
TI - Antimalarial Pyrido[1,2-a]benzimidazoles
T2 - Journal of Medicinal Chemistry
AU - Ndakala, Albert J
AU - Gessner, Richard K
AU - Gitari, Patricia W.
AU - October, Natasha
AU - WHITE, KAREN E.
AU - Hudson, Alan
AU - Fakorede, Foluke
AU - Shackleford, D.
AU - Kaiser, Marcel
AU - Yeates, Clive
AU - Charman, Susan C
AU - Chibale, Kelly
PY - 2011
DA - 2011/06/16
PB - American Chemical Society (ACS)
SP - 4581-4589
IS - 13
VL - 54
PMID - 21644541
SN - 0022-2623
SN - 1520-4804
ER -
BibTex |
Cite this
BibTex (up to 50 authors) Copy
@article{2011_Ndakala,
author = {Albert J Ndakala and Richard K Gessner and Patricia W. Gitari and Natasha October and KAREN E. WHITE and Alan Hudson and Foluke Fakorede and D. Shackleford and Marcel Kaiser and Clive Yeates and Susan C Charman and Kelly Chibale},
title = {Antimalarial Pyrido[1,2-a]benzimidazoles},
journal = {Journal of Medicinal Chemistry},
year = {2011},
volume = {54},
publisher = {American Chemical Society (ACS)},
month = {jun},
url = {https://doi.org/10.1021/jm200227r},
number = {13},
pages = {4581--4589},
doi = {10.1021/jm200227r}
}
MLA
Cite this
MLA Copy
Ndakala, Albert J., et al. “Antimalarial Pyrido[1,2-a]benzimidazoles.” Journal of Medicinal Chemistry, vol. 54, no. 13, Jun. 2011, pp. 4581-4589. https://doi.org/10.1021/jm200227r.
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