Publication
Title
Pharmacomodulation of the antimalarial plasmodione : synthesis of biaryl- and N-arylalkylamine analogues, antimalarial activities and physicochemical properties
Author
Abstract
With the aim of increasing the structural diversity on the early antimalarial drug plasmodione, an efficient and versatile procedure to prepare a series of biaryl- and N-arylalkylamines as plasmodione analogues is described. Using the naturally occurring and commercially available menadione as starting material, a 2-step sequence using a Kochi-Anderson reaction and subsequent Pd-catalyzed Suzuki-Miyaura coupling was developed to prepare three representative biphenyl derivatives in good yields for antimalarial evaluation. In addition, synthetic methodologies to afford 3-benzylmenadione derivatives bearing a terminal -N(Me)2 or -N(Et)2 in different positions (ortho, meta and para) on the aryl ring of the benzylic chain of plasmodione were investigated through reductive amination was used as the optimal route to prepare these protonable N-arylalkylamine privileged scaffolds. The antimalarial activities were evaluated and discussed in light of their physicochemical properties. Among the newly synthesized compounds, the para-position of the substituent remains the most favourable position on the benzyl chain and the carbamate -NHBoc was found active both in vitro (42 nM versus 29 nM for plasmodione) and in vivo in Plasmodium berghei-infected mice. The measured acido-basic features of these new molecules support the cytosol-food vacuole shuttling properties of non-protonable plasmodione derivatives essential for redox-cycling. These findings may be useful in antimalarial drug optimization.
Language
English
Source (journal)
Molecules: a journal of synthetic chemistry and natural product chemistry. - Bazel
Publication
Bazel : 2017
ISSN
1420-3049
DOI
10.3390/MOLECULES22010161
Volume/pages
22 :1 (2017) , 32 p.
Article Reference
161
ISI
000395473500158
Note
COST CM1307: Targeted Chemotherapy towards Diseases Caused by EndoparasitesProceedings in Medicinal and Natural Product Chemistry)
Medium
E-only publicatie
Full text (Publisher's DOI)
Full text (open access)
UAntwerpen
Faculty/Department
Research group
Publication type
Subject
Affiliation
Publications with a UAntwerp address
External links
Web of Science
Record
Identifier
Creation 23.01.2017
Last edited 28.01.2024
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