Carbon isosteres of the 4-aminopyridine substructure of chloroquine: effects on pK(a), hematin binding, inhibition of hemozoin formation, and parasite growth.
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.
Cheruku
Srinivasa R
SR
College of Pharmacy, University of Nebraska Medical Center, 986025 Nebraska Medical Center, Omaha, Nebraska 68198-6025, USA.
Maiti
Souvik
S
Dorn
Arnulf
A
Scorneaux
Bernard
B
Bhattacharjee
Apurba K
AK
Ellis
William Y
WY
Vennerstrom
Jonathan L
JL
D015761:4-Aminopyridine / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000494:pharmacology; D000818:Animals; D000962:Antimalarials / Q000138:chemical synthesis* / Q000494:pharmacology; D002738:Chloroquine / Q000737:chemistry*; D006427:Hemin / Q000737:chemistry*; D010963:Plasmodium falciparum / Q000187:drug effects* / Q000254:growth & development; D013329:Structure-Activity Relationship; D013816:Thermodynamics
D000962:Antimalarials; D006427:Hemin; D002738:Chloroquine; D015761:4-Aminopyridine