Antimalarial activity and mechanisms of action of two novel 4-aminoquinolines against chloroquine-resistant parasites.
Chloroquine (CQ) is a cost effective antimalarial drug with a relatively good safety profile (or therapeutic index). However, CQ is no longer used alone to treat patients with Plasmodium falciparum due to the emergence and spread of CQ-resistant strains, also reported for P. vivax. Despite CQ resistance, novel drug candidates based on the structure of CQ continue to be considered, as in the present work. One CQ analog was synthesized as monoquinoline (MAQ) and compared with a previously synthesized bisquinoline (BAQ), both tested against P. falciparum in vitro and against P. berghei in mice, then evaluated in vitro for their cytotoxicity and ability to inhibit hemozoin formation. Their interactions with residues present in the NADH binding site of P falciparum lactate dehydrogenase were evaluated using docking analysis software. Both compounds were active in the nanomolar range evaluated through the HRPII and hypoxanthine tests. MAQ and BAQ derivatives were not toxic, and both compounds significantly inhibited hemozoin formation, in a dose-dependent manner. MAQ had a higher selectivity index than BAQ and both compounds were weak PfLDH inhibitors, a result previously reported also for CQ. Taken together, the two CQ analogues represent promising molecules which seem to act in a crucial point for the parasite, inhibiting hemozoin formation.
Centro de Pesquisas René Rachou, Fundação Oswaldo Cruz, Belo Horizonte, Minas Gerais, Brazil.
Anna Caroline Campos
AC
Aguiar
Raquel de Meneses
Rde M
Santos
Flávio Júnior Barbosa
FJ
Figueiredo
Wilian Augusto
WA
Cortopassi
André Silva
AS
Pimentel
Tanos Celmar Costa
TC
França
Mario Roberto
MR
Meneghetti
Antoniana Ursine
AU
Krettli
D000634:Aminoquinolines / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D000962:Antimalarials / Q000737:chemistry / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002738:Chloroquine; D004305:Dose-Response Relationship, Drug; D004351:Drug Resistance / Q000502:physiology; D004797:Enzyme-Linked Immunosorbent Assay; D006420:Hemeproteins / Q000037:antagonists & inhibitors; D006801:Humans; D066298:In Vitro Techniques; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D008288:Malaria / Q000188:drug therapy*; D051379:Mice; D008958:Models, Molecular; D015394:Molecular Structure; D010962:Plasmodium berghei / Q000187:drug effects* / Q000378:metabolism; D010963:Plasmodium falciparum / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D011485:Protein Binding; D011487:Protein Conformation; D013778:Tetrazolium Salts; D013844:Thiazoles
D000634:Aminoquinolines; D000962:Antimalarials; D006420:Hemeproteins; D013778:Tetrazolium Salts; D013844:Thiazoles; C020753:hemozoin; D002738:Chloroquine; D007770:L-Lactate Dehydrogenase; C022616:thiazolyl blue; C001920:4-aminoquinoline