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6-Hydrophobic aromatic substituent pyrimethamine analogues as potential antimalarials for pyrimethamine-resistant Plasmodium falciparum.

Abstract：

:The series of des-Cl (unsubstituted) and m-Cl phenyl analogues of PYR with various flexible 6-substituents were synthesized and studied for the binding affinities with highly resistant quadruple mutant (QM) DHFR. The derivatives carrying 4 atoms linker with a terminal carboxyl substituted on the aromatic ring exhibited good inhibition to the QM enzyme and also showed effective antimalarial activities against resistant P. falciparum bearing the mutant enzymes with relatively low cytotoxicity to mammalian cells. The X-ray crystallographic analysis of the enzyme-inhibitor complexes suggested that the hydrophobic substituent at 6-position was accommodated well in the hydrophobic pocket and the optimal length of the flexible linker could effectively promote the binding of the terminal carboxyl group to the key amino acid residues, Arg59 and Arg122.

journal_name

Bioorg Med Chem

journal_title

Bioorganic & medicinal chemistry

authors

Saepua S,Sadorn K,Vanichtanankul J,Anukunwithaya T,Rattanajak R,Vitsupakorn D,Kamchonwongpaisan S,Yuthavong Y,Thongpanchang C

doi

10.1016/j.bmc.2019.115158

subject

Has Abstract

pub_date

2019-12-15 00:00:00

pages

115158

issue

24

eissn

0968-0896

issn

1464-3391

pii

S0968-0896(19)31188-5

journal_volume

27

pub_type

杂志文章

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