Design, synthesis, and biological evaluation of phosphinopeptides against Trypanosoma cruzi targeting trypanothione biosynthesis.
As a part of our project aimed at the search for new safe chemotherapeutic and chemoprophylactic agents against American trypanosomiasis (Chagas's disease), a series of phosphinopeptides structurally related to glutathione was designed, synthesized, and evaluated as antiproliferative agents against the parasite responsible for this disease, the hemoflagellated protozoan Trypanosoma cruzi. The rationale for the synthesis of these compounds was supported on the basis that the presence of the phosphinic acid moiety would mimic the tetrahedral transition state of trypanothione synthase (TryS), a typical C:N ligase, and the molecular target of these drugs. Of the designed compounds, 53 and 54 were potent growth inhibitors against the clinically more relevant form of T. cruzi (amastigotes) growing in myoblasts. The efficacy for these drugs was comparable to that exhibited by the well-known antiparasitic agent WC-9. The simple phosphinopeptide structure found as a pharmacophore in the present study constitutes a starting point for the development of straightforward optimized drugs.
Ravaschino
Esteban L
EL
Departamento de Química Orgánica, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Pabellón 2, Ciudad Universitaria, C1428EHA, Buenos Aires, Argentina.
Docampo
Roberto
R
Rodriguez
Juan B
JB
D019732:Amide Synthases / Q000037:antagonists & inhibitors; D000818:Animals; D000981:Antiprotozoal Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D049109:Cell Proliferation / Q000187:drug effects; D015195:Drug Design; D005978:Glutathione / Q000031:analogs & derivatives* / Q000096:biosynthesis / Q000187:drug effects; D015394:Molecular Structure; D021261:Parasitic Sensitivity Tests; D010455:Peptides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D010647:Phenyl Ethers / Q000494:pharmacology; D010721:Phosphinic Acids / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D013095:Spermidine / Q000031:analogs & derivatives* / Q000096:biosynthesis; D013329:Structure-Activity Relationship; D013861:Thiocyanates / Q000494:pharmacology; D014349:Trypanosoma cruzi / Q000737:chemistry / Q000187:drug effects* / Q000201:enzymology / Q000254:growth & development
C111921:4-phenoxyphenoxyethyl thiocyanate; D000981:Antiprotozoal Agents; D010455:Peptides; D010647:Phenyl Ethers; D010721:Phosphinic Acids; D013861:Thiocyanates; C044809:trypanothione; D019732:Amide Synthases; C064407:trypanothione synthetase; D005978:Glutathione; D013095:Spermidine