Polycyclic amines as chloroquine resistance modulating agents in Plasmodium falciparum. Issue 4 (15th February 2016)

• Record Type: Journal Article
• Authors: Joubert, Jacques; Kapp, Erika; Taylor, Dale; Smith, Peter J.; Malan, Sarel F.
• Is Part Of: Bioorganic & medicinal chemistry letters. Volume 26:Issue 4(2016)
• Page Start: 1151
• Page End: 1155
• Publication Date: 2016-02-15
• Subjects: Pentacycloundecylamine -- Adamantane amine -- Plasmodium falciparum -- Voltage-gated calcium channels -- Chemosensitizers; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; 572
• DOI: 10.1016/j.bmcl.2016.01.052
• Languages: English
• ISSNs: 0960-894X

Abstract

Graphical abstract: 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. Compounds2, 4, 5 and10 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). Compounds2 and10 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.