TY - JOUR
T1 - Optimization of propafenone analogues as antimalarial leads
AU - Lowes, David J.
AU - Guiguemde, W. Armand
AU - Connelly, Michele C.
AU - Zhu, Fangyi
AU - Sigal, Martina S.
AU - Clark, Julie A.
AU - Lemoff, Andrew S.
AU - Derisi, Joseph L.
AU - Wilson, Emily B.
AU - Guy, R. Kiplin
PY - 2011/11/10
Y1 - 2011/11/10
N2 - Propafenone, a class Ic antiarrythmic drug, inhibits growth of cultured Plasmodium falciparum. While the drug's potency is significant, further development of propafenone as an antimalarial would require divorcing the antimalarial and cardiac activities as well as improving the pharmacokinetic profile of the drug. A small array of propafenone analogues was designed and synthesized to address the cardiac ion channel and PK liabilities. Testing of this array revealed potent inhibitors of the 3D7 (drug sensitive) and K1 (drug resistant) strains of P. falciparum that possessed significantly reduced ion channel effects and improved metabolic stability. Propafenone analogues are unusual among antimalarial leads in that they are more potent against the multidrug resistant K1 strain of P. falciparum compared to the 3D7 strain.
AB - Propafenone, a class Ic antiarrythmic drug, inhibits growth of cultured Plasmodium falciparum. While the drug's potency is significant, further development of propafenone as an antimalarial would require divorcing the antimalarial and cardiac activities as well as improving the pharmacokinetic profile of the drug. A small array of propafenone analogues was designed and synthesized to address the cardiac ion channel and PK liabilities. Testing of this array revealed potent inhibitors of the 3D7 (drug sensitive) and K1 (drug resistant) strains of P. falciparum that possessed significantly reduced ion channel effects and improved metabolic stability. Propafenone analogues are unusual among antimalarial leads in that they are more potent against the multidrug resistant K1 strain of P. falciparum compared to the 3D7 strain.
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U2 - 10.1021/jm2005546
DO - 10.1021/jm2005546
M3 - Article
C2 - 21955244
AN - SCOPUS:80455144792
SN - 0022-2623
VL - 54
SP - 7477
EP - 7485
JO - Journal of Medicinal Chemistry
JF - Journal of Medicinal Chemistry
IS - 21
ER -