6-Hydrophobic aromatic substituent pyrimethamine analogues as potential antimalarials for pyrimethamine-resistant Plasmodium falciparum
| Autor: | Jarunee Vanichtanankul, Siriporn Saepua, Yongyuth Yuthavong, Roonglawan Rattanajak, Karoon Sadorn, Danoo Vitsupakorn, Tosapol Anukunwithaya, Sumalee Kamchonwongpaisan, Chawanee Thongpanchang |
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| Rok vydání: | 2019 |
| Předmět: |
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Molecular Protein Conformation Stereochemistry Plasmodium falciparum Clinical Biochemistry Mutant Drug Resistance Substituent Pharmaceutical Science 01 natural sciences Biochemistry Antimalarials chemistry.chemical_compound Oxidoreductase Chlorocebus aethiops Drug Discovery Animals Transferase Cytotoxicity Vero Cells Molecular Biology chemistry.chemical_classification Molecular Structure biology 010405 organic chemistry Organic Chemistry biology.organism_classification 0104 chemical sciences Tetrahydrofolate Dehydrogenase 010404 medicinal & biomolecular chemistry Pyrimethamine Enzyme chemistry Drug Design Folic Acid Antagonists Molecular Medicine Linker |
| Zdroj: | Bioorganic & Medicinal Chemistry. 27:115158 |
| ISSN: | 0968-0896 |
| DOI: | 10.1016/j.bmc.2019.115158 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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