Flexible diaminodihydrotriazine inhibitors of Plasmodium falciparum dihydrofolate reductase: Binding strengths, modes of binding and their antimalarial activities

Eur J Med Chem. 2020 Jun 1:195:112263. doi: 10.1016/j.ejmech.2020.112263. Epub 2020 Mar 25.


A series of flexible diaminodihydrotriazines or cycloguanil (Cyc) analogues are developed and shown to inhibit P. falciparum dihydrofolate reductase (PfDHFR) of the wild type or those carrying either single (S108N), double (C59R + S108N and A16V + S108T), triple (N51I + C59R + S108N and C59R + S108N + I164L) or quadruple (N51I + C59R + S108N + I164L) mutations, responsible for antifolate resistance. The flexibility of the side chain at position N1 has been included in the design so as to avoid unfavourable steric interaction with the side chain of residue 108 of the resistant mutants. The inhibition constants of many inhibitors for the mutant enzymes are in the low nanomolar region. Regaining of drug binding efficacies was achieved with both A16V and S108N series of mutants. X-ray studies of some enzyme-inhibitor complexes designed for optimal interaction with the mutant enzymes reveal the modes of binding in line with the Ki values. A number of these compounds show excellent antimalarial activities against resistant P. falciparum bearing the mutant enzymes, and exhibit low cytotoxicity to mammalian cells, making them good candidates for further development as antimalarial drugs.

Keywords: Cycloguanil; Diaminodihydrotriazine; Dihydrofolate reductase; Malaria; Plasmodium falciparum; WR99210.

MeSH terms

  • Antimalarials / chemistry*
  • Antimalarials / metabolism
  • Antimalarials / pharmacology*
  • Folic Acid Antagonists / chemistry*
  • Folic Acid Antagonists / metabolism
  • Folic Acid Antagonists / pharmacology*
  • Molecular Docking Simulation
  • Mutation
  • Protein Binding
  • Protein Conformation
  • Protozoan Proteins / antagonists & inhibitors*
  • Protozoan Proteins / chemistry
  • Protozoan Proteins / genetics
  • Protozoan Proteins / metabolism
  • Tetrahydrofolate Dehydrogenase / chemistry
  • Tetrahydrofolate Dehydrogenase / genetics
  • Tetrahydrofolate Dehydrogenase / metabolism
  • Triazines / chemistry*
  • Triazines / metabolism
  • Triazines / pharmacology*


  • Antimalarials
  • Folic Acid Antagonists
  • Protozoan Proteins
  • Triazines
  • DHFR protein, Plasmodium falciparum
  • Tetrahydrofolate Dehydrogenase