ABSTRACT
In a focused exploration, we designed, synthesized, and biologically evaluated chiral conjugated new chloroquine (CQ) analogues with substituted piperazines as antimalarial agents. In vitro as well as in vivo studies revealed that compound 7c showed potent activity (in vitro 50% inhibitory concentration, 56.98 nM for strain 3D7 and 97.76 nM for strain K1; selectivity index in vivo [up to at a dose of 12.5 mg/kg of body weight], 3,510) as a new lead antimalarial agent. Other compounds (compounds 6b, 6d, 7d, 7h, 8c, 8d, 9a, and 9c) also showed moderate activity against a CQ-sensitive strain (3D7) and superior activity against a CQ-resistant strain (K1) of Plasmodium falciparum Furthermore, we carried out docking and three-dimensional quantitative structure-activity relationship (3D-QSAR) studies of all in-house data sets (168 molecules) of chiral CQ analogues to explain the structure-activity relationships (SAR). Our new findings specify the significance of the H-bond interaction with the side chain of heme for biological activity. In addition, the 3D-QSAR study against the 3D7 strain indicated the favorable and unfavorable sites of CQ analogues for incorporating steric, hydrophobic, and electropositive groups to improve the antimalarial activity.
Subject(s)
Antimalarials/chemical synthesis , Chloroquine/analogs & derivatives , Heme/chemistry , Malaria/drug therapy , Piperazines/chemistry , Plasmodium falciparum/drug effects , Animals , Antimalarials/pharmacology , Chlorocebus aethiops , Chloroquine/chemical synthesis , Chloroquine/pharmacology , Drug Design , Drug Resistance/drug effects , Erythrocytes/drug effects , Erythrocytes/parasitology , Hemeproteins/antagonists & inhibitors , Hemeproteins/biosynthesis , Humans , Hydrophobic and Hydrophilic Interactions , Inhibitory Concentration 50 , Malaria/mortality , Malaria/parasitology , Mice , Molecular Docking Simulation , Parasitic Sensitivity Tests , Plasmodium falciparum/growth & development , Plasmodium falciparum/metabolism , Plasmodium yoelii/drug effects , Plasmodium yoelii/growth & development , Plasmodium yoelii/metabolism , Static Electricity , Stereoisomerism , Structure-Activity Relationship , Survival Analysis , Vero CellsABSTRACT
A series of short chain 4-aminoquinoline-imidazole derivatives have been synthesized in one pot two step multicomponent reaction using van leusen standard protocol. The diethylamine function of chloroquine is replaced by substituted imidazole derivatives containing tertiary terminal nitrogen. All the synthesized compounds were screened against the chloroquine sensitive (3D7) and chloroquine resistant (K1) strains of Plasmodium falciparum. Some of the compounds (6, 8, 9 and 17) in the series exhibited comparable activity to CQ against K1 strain of P. falciparum. All the compounds displayed resistance factor between 0.09 and 4.57 as against 51 for CQ. Further, these analogues were found to form a strong complex with hematin and inhibit the ß-hematin formation, therefore these compounds act via heme polymerization target.
Subject(s)
Aminoquinolines/chemistry , Antimalarials/chemical synthesis , Drug Design , Imidazoles/chemistry , Animals , Antimalarials/chemistry , Antimalarials/pharmacology , Cell Survival/drug effects , Chlorocebus aethiops , Drug Resistance/drug effects , Hemin/antagonists & inhibitors , Hemin/metabolism , Imidazoles/chemical synthesis , Imidazoles/pharmacology , Plasmodium falciparum/drug effects , Structure-Activity Relationship , Vero CellsABSTRACT
A novel 4-aminoquinoline derivative [(S)-7-chloro-N-(4-methyl-1-(4-methylpiperazin-1-yl)pentan-2-yl)-quinolin-4-amine triphosphate] exhibiting curative activity against chloroquine-resistant malaria parasites has been identified for preclinical development as a blood schizonticidal agent. The lead molecule selected after detailed structure-activity relationship (SAR) studies has good solid-state properties and promising activity against in vitro and in vivo experimental malaria models. The in vitro absorption, distribution, metabolism, and excretion (ADME) parameters indicate a favorable drug-like profile.
