2. Academic Validation
  3. Adamantane amine-linked chloroquinoline derivatives as chloroquine resistance modulating agents in Plasmodium falciparum

Adamantane amine-linked chloroquinoline derivatives as chloroquine resistance modulating agents in Plasmodium falciparum

  • Bioorg Med Chem Lett. 2018 May 1;28(8):1287-1291. doi: 10.1016/j.bmcl.2018.03.026.
Opute M Yvette 1,  Sarel F Malan 1,  Dale Taylor 2,  Erika Kapp 1,  Jacques Joubert 3
Affiliations

Affiliations

  • 1 Pharmaceutical Chemistry, School of Pharmacy, University of the Western Cape, Private Bag X17, Bellville, South Africa.
  • 2 Division of Clinical Pharmacology, Department of Medicine, University of Cape Town, Groote Schuur Hospital, Observatory 7925, South Africa.
  • 3 Pharmaceutical Chemistry, School of Pharmacy, University of the Western Cape, Private Bag X17, Bellville, South Africa. Electronic address: jjoubert@uwc.ac.za.
PMID: 29559277 DOI: 10.1016/j.bmcl.2018.03.026
Abstract

Previously we have shown that pentacycloundecylamine-chloroquinoline (PCU-CQ) conjugates possess significant chemosensitizing abilities and can circumvent the resistance associated with chloroquine (CQ) resistant plasmodia. In order to further explore structurally related polycyclic compounds as reversed CQ agents we synthesized a series of eight aza-adamantanol (1-4) and adamantane-imine (5-8) CQ conjugates. All conjugates showed limited cytotoxicity against CHO cells (IC50 > 37 µM). Compounds 1, 2 and 5 were highly active (K1 IC50 < 100 nM) exhibiting a 3-4-fold increase in antiplasmodial activity against CQ resistant strain K1 compared to CQ. Reduced cross-resistance (resistance index, RI: 2-4.3) relative to CQ (RI = 38) was also observed for these compounds. Compound 1 which showed an 18-fold enhancement at retaining its activity against the K1 strain compared to CQ is a promising candidate to substitute CQ in P. falciparum resistant malaria.

Keywords

Adamantanes; Chemosensitizers; Plasmodium falciparum; Resistance reversal agents.

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