Carbon Isosteres of the 4-Aminopyridine Substructure of Chloroquine: Effects on pKa, Hematin Binding, Inhibition of Hemozoin Formation, and Parasite Growth
- 6 June 2003
- journal article
- Published by American Chemical Society (ACS) in Journal of Medicinal Chemistry
- Vol. 46 (14), 3166-3169
- https://doi.org/10.1021/jm030038x
Abstract
Unlike diprotic chloroquine (CQ), its two 4-aminoquinoline carbon isosteres (1, 2) are monoprotic at physiological pH. Compared to CQ, hematin binding affinity of 1 decreased 6.4-fold, and there was no measurable binding for 2. Although 1 was a weak inhibitor of hemozoin formation, neither isostere inhibited P. falciparum in vitro. Evidently, the CQ-hematin interaction is largely a function of its pyridine substructure, but inhibition of hemozoin formation and parasite growth depends on its 4-aminopyridine substructure.Keywords
This publication has 19 references indexed in Scilit:
- Solution Structures of Antimalarial Drug−Heme ComplexesBiochemistry, 2002
- Chloroquine‐Resistant MalariaThe Journal of Infectious Diseases, 2001
- Molecular ElectrostaticsChemical Reviews, 1995
- Malarial haemozoin/β-haematin supports haem polymerization in the absence of proteinNature, 1995
- Graphical AbstractEuropean Journal of Inorganic Chemistry, 1994
- Arene—Arene Interactions: Electrostatic or Charge Transfer?Angewandte Chemie, 1993
- Temperature Dependence of the Acid Dissociation Constants of ChloroquineJournal of Pharmaceutical Sciences, 1987
- Photochemical studies of 7-cis-rhodopsin at low temperatures. Nature and properties of the bathointermediateBiochemistry, 1980
- Human Malaria Parasites in Continuous CultureScience, 1976
- Deaza analogs of some 4-, 6-, and 8-aminoquinolinesJournal of Medicinal Chemistry, 1973