ABSTRACT
There is an urgent need for the development of new drugs to treat Chagas' disease, which is caused by the protozoan parasite Trypanosoma cruzi. The enzyme dihydrofolate reductase (DHFR) has been a very successful drug target in a number of diseases and we decided to investigate it as a potential drug target for Chagas' disease. A homology model of the enzyme was used to search the Cambridge Structural Database using the program DOCK 3.5. Compounds were then tested against the enzyme and the whole parasite. Compounds were also screened against the related parasite, Trypanosoma brucei.
Subject(s)
Enzyme Inhibitors/chemistry , Enzyme Inhibitors/pharmacology , Tetrahydrofolate Dehydrogenase/metabolism , Trypanosoma cruzi/drug effects , Trypanosoma cruzi/enzymology , Animals , Cell Line , Chagas Disease/drug therapy , Chagas Disease/parasitology , Databases as Topic , Disease Models, Animal , Drug Design , Drug Evaluation, Preclinical , Enzyme Inhibitors/therapeutic use , Folic Acid Antagonists/chemistry , Folic Acid Antagonists/pharmacology , Folic Acid Antagonists/therapeutic use , Inhibitory Concentration 50 , Mice , Muscles/cytology , Rats , Trypanosoma brucei rhodesiense/drug effectsABSTRACT
The program DOCK3.5 was used to search the Cambridge Structural Database for novel inhibitors of Leishmanial dihydrofolate reductase. A number of compounds were obtained and screened against the enzyme and against the intact parasite Leishmania donovani and the related organisms Trypanosoma brucei and Trypanosoma cruzi. The compounds screened showed weak activity in both the enzyme assays and the in vitro assays.
Subject(s)
Leishmania donovani/drug effects , Oxadiazoles/pharmacology , Pyrimidines/pharmacology , Tetrahydrofolate Dehydrogenase/drug effects , Trypanocidal Agents/pharmacology , Trypanosoma brucei brucei/drug effects , Trypanosoma cruzi/drug effects , Animals , Crystallography, X-Ray , Databases as Topic , Drug Evaluation, Preclinical , Enzyme Inhibitors/pharmacology , Humans , Inhibitory Concentration 50 , Leishmania donovani/enzymology , Mice , Molecular Structure , Parasites/drug effects , Rats , Recombinant ProteinsABSTRACT
In this paper the solid phase synthesis of various substituted purines is described starting from 4,6-dichloro-5-nitropyrimidine. The 4,6-dichloro-5-nitropyrimidine was coupled to Rink amide resin followed by displacement of the second chloride by an amino compound. Reduction of the nitro compound proved to be problematic but was achieved using lithium aluminum hydride/aluminum trichloride. The diamines (13) were then elaborated to purines by three different routes.
