Endoperoxide-8-aminoquinoline hybrids as dual-stage antimalarial agents with enhanced metabolic stability.

Abstract

Hybrid compounds may play a critical role in the context of the malaria eradication agenda, which will benefit from therapeutic tools active against the symptomatic erythrocytic stage of Plasmodium infection, and also capable of eliminating liver stage parasites. To address the need for efficient multistage antiplasmodial compounds, a small library of 1,2,4,5-tetraoxane-8- aminoquinoline hybrids, with the metabolically labile C-5 position of the 8-aminoquinoline moiety blocked with aryl groups, was synthesized and screened for antiplasmodial activity and metabolic stability. The hybrid compounds inhibited development of intra-erythrocytic forms of the multidrug-resistant Plasmodium falciparum W2 strain, with EC50 values in the nM range, and with low cytotoxicity against mammalian cells. The compounds also inhibited the development of P. berghei liver stage parasites, with the most potent compounds displaying EC50 values in the low μM range. SAR analysis revealed that unbranched linkers between the endoperoxide and 8-aminoquinoline pharmacophores are most beneficial for dual antiplasmodial activity. Importantly, hybrids were significantly more potent than a 1:1 mixture of 8-aminoquinoline-tetraoxane, highlighting the superiority of the hybrid approach over the combination therapy. Furthermore, aryl substituents at C-5 of the 8-aminoquinoline moiety improve the compounds' metabolic stability when compared with their primaquine (i.e. C-5 unsubstituted) counterparts. Overall, this study reveals that blocking the quinoline C-5 position does not result in loss of dual-stage antimalarial activity, and that tetraoxane-8- aminoquinoline hybrids are an attractive approach to achieve elimination of exo- and intraerythrocytic parasites, thus with the potential to be used in malaria eradication campaigns.

• Authors: Rita Capela, Joana Magalhães, Daniela Miranda, Marta Machado, Margarida Sanches-Vaz, Inês S Albuquerque, Moni Sharma, Jiri Gut, Philip J Rosenthal, Raquel Frade, Maria J Perry, Rui Moreira, Miguel Prudêncio, Francisca Lopes
• Journal: European journal of medicinal chemistry (Eur J Med Chem) Vol. 149 Pg. 69-78 (Apr 10 2018) ISSN: 1768-3254 [Electronic] France
• PMID: 29499488 (Publication Type: Journal Article)
• Copyright: Copyright © 2018 Elsevier Masson SAS. All rights reserved.

Chemical References

• Aminoquinolines
• Antimalarials
• Peroxides
• Small Molecule Libraries
• 8-aminoquinoline

Topics

• Aminoquinolines (chemistry, metabolism, therapeutic use)
• Animals
• Antimalarials (chemical synthesis, metabolism, pharmacology)
• Drug Evaluation, Preclinical
• Drug Stability
• Erythrocytes (parasitology)
• Humans
• Liver (parasitology)
• Peroxides (chemistry, metabolism)
• Plasmodium berghei (drug effects)
• Plasmodium falciparum (drug effects)
• Small Molecule Libraries (chemical synthesis)
• Structure-Activity Relationship