Synthesis and in vivo antimalarial activity of novel naphthoquine derivatives with linear/cyclic structured pendants.

Future Medicinal Chemistry
Ling TangHongquan Wang

Abstract

Naphthoquine (NQ) was discovered by our institute as an antimalarial candidate in 1980s, and currently employed as an artemisinin-based combination therapy partner drug. Resistance to NQ was found in mouse model in laboratory, and might emerge in future as widely used. We herein report the design and synthesis of NQ derivatives by replacing t-butyl moiety with linear/cyclic structured pendants. All the target compounds 6a-l and intermediates 5a-h were tested for their in vivo antimalarial activity against Plasmodium berghei K173 strain in mice. Compounds 6a and 6j were found to have a comparable or slightly more potent activity (the 50% effective dose [ED50], which is required to decrease parasitemia by 50%: 0.38-0.43 mg/kg) than NQ (ED50: 0.48 mg/kg). The newly designed compounds 6a and 6j might be promising antimalarial candidates for further research.

References

Jun 16, 2006·Malaria Journal·Carol Hopkins Sibley, Pascal Ringwald
Sep 28, 2010·Experimental Parasitology·Hong WangWu-Chun Cao
Feb 15, 2012·Antimicrobial Agents and Chemotherapy·Kevin T BattyTimothy M E Davis
Apr 17, 2013·Bioorganic & Medicinal Chemistry Letters·Marco A BiamonteKarine G Le Roch
May 23, 2014·Drug Discovery Today. Technologies·Francisco-Javier Gamo
Aug 2, 2014·European Journal of Medicinal Chemistry·Ajay KumarDhirender Kaushik
Apr 15, 2016·Drugs·Brioni R MooreTimothy M E Davis
Oct 22, 2016·Cell·Alan F CowmanKevin Marsh

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Methods Mentioned

BETA
silicagel
column chromatography

Software Mentioned

R
drc package
drc package of

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