Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2009 Dec 15;19(24):6970-4.
doi: 10.1016/j.bmcl.2009.10.050. Epub 2009 Oct 29.

Cell-based optimization of novel benzamides as potential antimalarial leads

Tao Wu  1 , Advait Nagle, Tomoyo Sakata, Kerstin Henson, Rachel Borboa, Zhong Chen, Kelli Kuhen, David Plouffe, Elizabeth Winzeler, Francisco Adrian, Tove Tuntland, Jonathan Chang, Susan Simerson, Steven Howard, Jared Ek, John Isbell, Xianming Deng, Nathanael S Gray, David C Tully, Arnab K Chatterjee
Affiliations

Cell-based optimization of novel benzamides as potential antimalarial leads

Tao Wu et al. Bioorg Med Chem Lett. .

Abstract

Screening our in-house compound collection using a cell based Plasmodium falciparum proliferation assay we discovered a known pan-kinase inhibitor scaffold as a hit. Further optimization of this series led us to a novel benzamide scaffold which was devoid of human kinase activity while retaining its antiplasmodial activity. The evolution of this compound series leading to optimized candidates with good cellular potency against multiple strains as well as decent in vivo profile is described in this Letter.

PubMed Disclaimer

Figures

None
Graphical abstract
Scheme 1
Scheme 1
Proprietary kinase scaffolds offered hits: piperidine benzamides.
Scheme 2
Scheme 2
General synthesis scheme of piperidyl benzamides amides. Reagents and conditions: (a) K2CO3, DMSO, 80 °C; (b) 50% H2SO4, reflux, 78%, 2 steps; (c) RNH2, HATU, DIEA, DMF, 23 °C, 60–70%.
Scheme 3
Scheme 3
General synthesis scheme of piperidyl benzamides reverse amides, sulfonamides and ureas. Reagents and conditions: (a) (i) DPPA, Et3N, t-BuOH, reflux; (ii) TFA, DCM, 23 °C, 33%; (b) R′CO2H, HATU, DIEA, DMF, 23 °C; or R′SO2Cl, DIEA, CH2Cl2; or R′NCO, toluene, 80 °C, 40–80%.
Scheme 4
Scheme 4
General synthesis scheme of piperidyl benzamides amine SAR. Reagents and conditions: (a) (i) SOCl2, CHCl3, reflux; (ii) aniline, pyridine, 72–79%; (b) Pd2(dba)3, BINAP, t-BuOK, toluene, 100 °C, 45–84%.
None
None
None
None
None
See this image and copyright information in PMC

References

    1. WHO ‘World Malaria Report 2008’, June 5, 2009, http://apps.who.int/malaria/wmr2008/malaria2008.pdf.
    1. Noedl H., Se Y., Schaecher K., Smith B.L., Socheat D., Fukuda M. New Eng. J. Med. 2008;359:2619. - PubMed
    1. Gelb M. Curr. Opin. Chem. Biol. 2007;11:440. - PMC - PubMed
    1. Wu, T.; Nagle, A.; Sakata, T.; Deng, X.; Chen, Z.; Henson, K.; Chang, J.; Plouffe, D.; Tuntland, T.; Kuhen, K.; Winzeler, E.; Gray, N.; Chatterjee, A. K. Abstract of Papers, 236th National Meeting of the American Chemical Society, Philadelphia, PA, August 2008. MEDI-339.
    1. Plouffe D., Brinker A., McNamara C., Henson K., Kato N., Kuhen K., Nagle A., Adrian F., Matzen J.T., Anderson P., Nam T., Gray N.S., Chatterjee A., Janes J., Yan S.F., Trager R., Caldwell J.S., Schultz P.G., Zhou Y., Winzeler E.A. Proc. Natl. Acad. Sci. U.S.A. 2008;105:9059. - PMC - PubMed

Publication types

MeSH terms

LinkOut - more resources