Targeting the erythrocytic and liver stages of malaria parasites with s-triazine-based hybrids.

Abstract

A diversity-oriented library of s-triazine-based hybrids was screened for activity against the chloroquine-resistant Plasmodium falciparum W2 strain. The most striking result was sub-micromolar activity against cultured erythrocytic-stage parasites of hybrid molecules containing one or two 8-aminoquinoline moieties. These compounds were not clearly toxic to human cells. The most effective blood-schizontocidal s-triazine derivatives were then screened for activity against the liver stage of malaria parasites. The s-triazine hybrid containing two 8-aminoquinoline moieties and one chlorine atom emerged as the most potent against P. berghei liver-stage infection, active in the low nanomolar region, combined with good metabolic stability in rat liver microsomes. These results indicate that s-triazine-8-aminoquinoline-based hybrids are excellent starting points for lead optimization as dual-stage antimalarials.

• Authors: Catarina A B Rodrigues, Raquel F M Frade, Inês S Albuquerque, Maria J Perry, Jiri Gut, Marta Machado, Philip J Rosenthal, Miguel Prudêncio, Carlos A M Afonso, Rui Moreira
• Journal: ChemMedChem (ChemMedChem) Vol. 10 Issue 5 Pg. 883-90 (May 2015) ISSN: 1860-7187 [Electronic] Germany
• PMID: 25784585 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Chemical References

• Antimalarials
• Triazines

Topics

• Animals
• Antimalarials (chemistry, pharmacology)
• CHO Cells
• Cell Line, Tumor
• Cell Proliferation
• Cricetinae
• Cricetulus
• Dose-Response Relationship, Drug
• Erythrocytes (parasitology)
• Humans
• Liver (parasitology)
• Malaria (drug therapy, parasitology)
• Parasitic Sensitivity Tests
• Plasmodium berghei (drug effects)
• Plasmodium falciparum (drug effects)
• Rats
• Structure-Activity Relationship
• Triazines (chemistry, pharmacology)