NDLI: New antimalarial 3-methoxy-1,2-dioxanes: optimization of cellular pharmacokinetics and pharmacodynamics properties by incorporation of amino and N-heterocyclic moieties at C4

Content Provider	Royal Society of Chemistry (RSC)
Author	Dato, A. Di Trombini, C. Lombardo, M. Dhavale, D. D. Persico, M. Fattorusso, C. Quintavalla, A. Taramelli, D. Sonawane, D. P. Corbett, Y. Chianese, G. Taglialatela-Scafati, O.
Copyright Year	2015
Abstract	A new series of nineteen 3-methoxy-1,2-dioxanes containing an amino moiety at C4 was designed, synthesized and tested for in vitro antimalarial activity against chloroquine sensitive (CQ-S) D10 and chloroquine resistant (CQ-R) W2 strains of Plasmodium falciparum (Pf). Cytotoxicity against the human endothelial cell line (HMEC-1) was also evaluated. The introduced modifications resulted in a notable improvement of the antimalarial activity. In particular, compound 9a with an amino-imidazole side-chain at C4 displays antimalarial activity in the high nanomolar range against the CQ-R Pf strain (W2 IC50 = 200 nM), being more active against CQ-R than CQ-S Pf strains and devoid of cytotoxicity against human HMEC-1 cells. On the other hand, some of the hybrids with 4-amino-7-chloroquinoline (9k–p) show an IC50 comparable to that of chloroquine against the CQ-S Pf strain (9k–p, D10 IC50 = 50–90 nM) but without losing potency against the CQ-R Pf strain (9k–p, resistance index = 1.2–2.6), with low cytotoxicity against HMEC-1. Structure–activity relationship studies show that the improved antimalarial activity of the new compounds is the result of a combination of cellular pharmacokinetics and pharmacodynamics effects.
Starting Page	72995
Ending Page	73010
Page Count	16
File Format	HTM / HTML PDF
ISSN	20462069
Volume Number	5
Issue Number	89
Journal	RSC Advances
DOI	10.1039/c5ra10785g
Language	English
Publisher	Royal Society of Chemistry
Access Restriction	Open
Subject Keyword	Plasmodium Pharmacodynamics Chloroquine IC50 Structure\u2013activity relationship Cytotoxicity Pharmacokinetics Methoxy group Endothelium
Content Type	Text
Resource Type	Article
Subject	Chemistry Chemical Engineering

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