title: Polycyclic amines as chloroquine resistance modulating agents in Plasmodium falciparum.
abstract: Pentacycloundecylamines (PCUs) and adamantane amines, such as NGP1-01 (1) and amantadine, have shown significant channel blocking activities. They are postulated to act as chemosensitizers and circumvent the resistance of the plasmodia parasite against chloroquine (CQ) by inhibiting the p-glycoprotein efflux pump and enabling the accumulation of CQ inside the parasite digestive vacuole. Twelve polycyclic amines containing either a PCU or adamantane amine moiety conjugated to different aromatic functionalities through various tethered linkers were selected based on their channel blocking abilities and evaluated as potential chemosensitizers. Compounds 2, 4, 5 and 10 showed significant voltage-gated calcium channel (VGCC) blocking ability (IC50=0.27-35 μM) and were able to alter the CQ IC50 in differing degrees (45-81%) in the multidrug resistant Plasmodium falciparum Dd2 isolate. Among them, the PCU-dansyl amine compound (4) displayed the best potential to act as a chemosensitizer against the Dd2 strain at a 1 μM concentration (RMI=0.19) while displaying moderate antiplasmodial activity (Dd2 IC50=6.25 μM) and low in vitro cytotoxicity against a mammalian cell line (CHO, IC50=119 μM). Compounds 2 and 10 also showed some promising chemosensitizing abilities (RMI=0.36 and 0.35 respectively). A direct correlation was found between the VGCC blocking ability of these polycyclic amines and their capacity to act as CQ resistance modulating agents.
authors.affiliation: Pharmaceutical Chemistry, School of Pharmacy, University of the Western Cape, Private Bag X17, Bellville 7535, South Africa. Electronic address: jjoubert@uwc.ac.za.
authors.forename: Jacques
authors.initials: J
authors.lastname: Joubert
authors.affiliation: Pharmaceutical Chemistry, School of Pharmacy, University of the Western Cape, Private Bag X17, Bellville 7535, South Africa.
authors.forename: Erika
authors.initials: E
authors.lastname: Kapp
authors.affiliation: Division of Clinical Pharmacology, Department of Medicine, University of Cape Town, Groote Schuur Hospital, Observatory 7925, South Africa.
authors.forename: Dale
authors.initials: D
authors.lastname: Taylor
authors.affiliation: Division of Clinical Pharmacology, Department of Medicine, University of Cape Town, Groote Schuur Hospital, Observatory 7925, South Africa.
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Smith
authors.affiliation: Pharmaceutical Chemistry, School of Pharmacy, University of the Western Cape, Private Bag X17, Bellville 7535, South Africa.
authors.forename: Sarel F
authors.initials: SF
authors.lastname: Malan
mesh_terms: D000218:Adamantane / Q000737:chemistry; D000588:Amines / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D000818:Animals; D000962:Antimalarials / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D016466:CHO Cells; D015220:Calcium Channels / Q000737:chemistry / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D002738:Chloroquine / Q000494:pharmacology; D006224:Cricetinae; D003412:Cricetulus; D004351:Drug Resistance / Q000187:drug effects; D020128:Inhibitory Concentration 50; D010963:Plasmodium falciparum / Q000187:drug effects; D011485:Protein Binding; D013329:Structure-Activity Relationship
chemical_list: D000588:Amines; D000962:Antimalarials; D015220:Calcium Channels; D002738:Chloroquine; D000218:Adamantane
keywords: Adamantane amine; Chemosensitizers; Pentacycloundecylamine; Plasmodium falciparum; Voltage-gated calcium channels