title: Inhibitors of multiple mutants of Plasmodium falciparum dihydrofolate reductase and their antimalarial activities.
abstract: Novel analogues of pyrimethamine (Pyr) and cycloguanil (Cyc) have been synthesized and tested as inhibitors of Plasmodium falciparum dihydrofolate reductase carrying triple (N51I+C59R+S108N, C59R+S108N+I164L) and quadruple (N51I+C59R+S108N+I164L) mutations responsible for antifolate resistance. The inhibitors were designed to avoid steric clash of the p-Cl group of the inhibitors with the side chain of Asn108, augmented by additional mutations of the resistant mutants. Cycloguanil derivatives were also designed to avoid steric clash with the side chain of Val16 in the A16V+S108T mutant. Many compounds have inhibition constants (K(i)) at the low nanomolar level against the mutant enzymes and a number have good antimalarial activities against resistant P. falciparum parasites bearing multiple mutations in the S108N series and A16V+S108T mutant enzymes. These compounds in the Pyr and Cyc series exhibit low and moderate cytotoxicity to nontumor (Vero) and tumor (KB, BC) cell lines. Some of these inhibitors are therefore potential candidates for further development as antimalarials.
authors.affiliation: National Center for Genetic Engineering and Biotechnology, National Science and Technology Development Agency, Pathumthani 12120, Thailand.
authors.forename: Sumalee
authors.initials: S
authors.lastname: Kamchonwongpaisan
authors.forename: Rachel
authors.initials: R
authors.lastname: Quarrell
authors.forename: Netnapa
authors.initials: N
authors.lastname: Charoensetakul
authors.forename: Rachel
authors.initials: R
authors.lastname: Ponsinet
authors.forename: Tirayut
authors.initials: T
authors.lastname: Vilaivan
authors.forename: Jarunee
authors.initials: J
authors.lastname: Vanichtanankul
authors.forename: Bongkoch
authors.initials: B
authors.lastname: Tarnchompoo
authors.forename: Worachart
authors.initials: W
authors.lastname: Sirawaraporn
authors.forename: Gordon
authors.initials: G
authors.lastname: Lowe
authors.forename: Yongyuth
authors.initials: Y
authors.lastname: Yuthavong
mesh_terms: D000818:Animals; D000962:Antimalarials / Q000138:chemical synthesis* / Q000494:pharmacology / Q000633:toxicity; D002460:Cell Line; D002522:Chlorocebus aethiops; D004351:Drug Resistance; D005493:Folic Acid Antagonists / Q000138:chemical synthesis* / Q000494:pharmacology / Q000633:toxicity; D006801:Humans; D009154:Mutation; D010963:Plasmodium falciparum / Q000201:enzymology*; D002727:Proguanil; D011739:Pyrimethamine / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000494:pharmacology / Q000633:toxicity; D013329:Structure-Activity Relationship; D013762:Tetrahydrofolate Dehydrogenase / Q000235:genetics*; D014227:Triazines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology
chemical_list: D000962:Antimalarials; D005493:Folic Acid Antagonists; D014227:Triazines; C026009:cycloguanil; D013762:Tetrahydrofolate Dehydrogenase; D002727:Proguanil; D011739:Pyrimethamine