Target guided synthesis of 5-benzyl-2,4-diamonopyrimidines: their antimalarial activities and binding affinities to wild type and mutant dihydrofolate reductases from Plasmodium falciparum.
The resistance to pyrimethamine (PYR) of Plasmodium falciparum arising from mutation at position 108 of dihydrofolate reductase (pfDHFR) from serine to asparagine (S108N) is due to steric interaction between the bulky side chain of N108 and Cl atom of the 5-p-Cl aryl group of PYR, which consequently resulted in the reduction in binding affinity between the enzyme and inhibitor. Molecular modeling suggested that the flexible antifolate, such as trimethoprim (TMP) derivatives, could avoid this steric constraint and should be considered as new, potentially effective compounds. The hydrophobic interaction between the side chain of inhibitor and the active site of the enzyme around position 108 was enhanced by the introduction of a longer and more hydrophobic side chain on TMP's 5-benzyl moiety. The prepared compounds, especially those bearing aromatic substituents, exhibited better binding affinities to both wild type and mutant enzymes than the parent compound. Binding affinities of these compounds correlated well with their antimalarial activities against both wild type and resistant parasites. Molecular modeling of the binding of such compounds with pfDHFR also supported the experimental data and clearly showed that aromatic substituents play an important role in enhancing binding affinity. In addition, some compounds with 6-alkyl substituents showed relatively less decrease in binding constants with the mutant enzymes and relatively good antimalarial activities against the parasites bearing the mutant enzymes.
Sirichaiwat
Chawanee
C
National Center for Genetic Engineering and Biotechnology, National Science and Technology Development Agency, 113 Thailand Science Park, Pahonyothin Road, Klong 1, Klongluang, Pathumtani 12120, Thailand.
Intaraudom
Chakapong
C
Kamchonwongpaisan
Sumalee
S
Vanichtanankul
Jarunee
J
Thebtaranonth
Yodhathai
Y
Yuthavong
Yongyuth
Y
D000818:Animals; D000962:Antimalarials / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D005493:Folic Acid Antagonists / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D008958:Models, Molecular; D009154:Mutation; D010963:Plasmodium falciparum / Q000187:drug effects / Q000201:enzymology*; D011485:Protein Binding; D011743:Pyrimidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship; D013762:Tetrahydrofolate Dehydrogenase / Q000235:genetics*; D014295:Trimethoprim / Q000031:analogs & derivatives / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology
D000962:Antimalarials; D005493:Folic Acid Antagonists; D011743:Pyrimidines; D014295:Trimethoprim; D013762:Tetrahydrofolate Dehydrogenase