Abstract: The present invention relates to 2,4-diamino-6-ethylpyrimidine derivatives that are inhibitors of wild type and quadruple mutant dihydrofolate reductase (DHFR) of Plasmodium falciparum. They also show in vitro antimalarial activities against Plasmodium falciparum for both wild type and mutant that are comparable to or better than pyrimethamine. In addition, the compounds of the present invention show a good selectivity to Plasmodium falciparum and exhibit lower cytotoxicity than pyrimethamine.

Abstract: The present invention relates to 2,4-diamino-6-ethylpyrimidine derivatives that are inhibitors of wild type and quadruple mutant dihydrofolate reductase (DHFR) of Plasmodium falciparum. They also show in vitro antimalarial activities against Plasmodium falciparum for both wild type and mutant that are comparable to or better than pyrimethamine. In addition, the compounds of the present invention show a good selectivity to Plasmodium falciparum and exhibit lower cytotoxicity than pyrimethamine.

Abstract: In this invention, cell lines are created for enzyme inhibitory testing of inhibitors against Plasmodium falciparum DHFR-TS and HPPK-DHPS. Provided the complementing DHFR-TS and HPPK-DHPS have sufficient activities to support growth of the surrogates in un-supplemented medium, the same surrogates could be used for screening inhibitors of targets against other parasite and pathogen species e.g. Plasmodium vivax, Trypanosoma brucei, Trypanosoma cruzi, Toxoplasma gondii or Mycobacterium tuberculosis. The cell lines in this invention are Escherichia coli strain whose thyA, folA, folK, and folP genes were disrupted using genetic knockout coupled with elimination of antibiotic resistance markers. The thyA KO, folP KO, folK KO, thyAfolA KO, folKfolP KO, thyAfolAfolP KO, thyAfolAfolK KO and thyAfolAfolKfolP KO E.

Abstract: The objective of this invention is to create a double thyA folA knockout Escherichia coli (E. coli) strain for antifolate screening against DHFR of malaria and other parasites. This strain is used together with a plasmid expressing DHFR-TS from the desired pathogenic organism, which constitutes an anti-DHFR assay against the pathogenic organism of interest. The benefit of this invention is that there is no interference from either host DHFR or trimethoprim, a bacterial DHFR inhibitor. This tool is easy to use and maintain. It provides quick and reliable results as compared with conventional anti-malarial and anti-parasitic assays. This invention should facilitate discovery of new anti-DHFR compounds against malaria and other parasitic diseases.

Abstract: In this invention, cell lines are created for enzyme inhibitory testing of inhibitors against Plasmodium falciparum DHFR-TS and HPPK-DHPS. Provided the complementing DHFR-TS and HPPK-DHPS have sufficient activities to support growth of the surrogates in un-supplemented medium, the same surrogates could be used for screening inhibitors of targets against other parasite and pathogen species e.g. Plasmodium vivax, Trypanosoma brucei, Trypanosoma cruzi, Toxoplasma gondii or Mycobacterium tuberculosis. The cell lines in this invention are Escherichia coli strain whose thyA, folA, folK, and folP genes were disrupted using genetic knockout coupled with elimination of antibiotic resistance markers. The thyA KO, folP KO, folK KO, thyAfolA KO, folKfolP KO, thyAfolAfolP KO, thyAfolAfolK KO and thyAfolAfolKfolP KO E.

Abstract: The present invention is anti-folate antimalarials with dual-binding modes of the general formula (I) [refer to structure in the abstract] wherein R1 and R2 which may be the same or different are independently selected from methyl or ethyl or alkylphenyl, R3 is independently hydrogen, halide, lower alkyl substituted with ester, carboxylic, amide, and ether. Linker is X(CH2)nY wherein X and Y which may be the same or different are independently selected from oxygen, carbon, nitrogen, substituted phenyl where n is an integer from 1 to 2-6, or pharmaceutically acceptable salts therefore. The anti-folate antimalarials with dual-binding modes act as novel inhibitors with good inhibition constants against wild-type, double (C59R+SIOSN), triple (N51+C59R+SIOSN, C59R+S 1 OSN+I164L), and quadruple (N51+C59R+S108N+I164L) mutant enzymes. The compounds are also effective against wild type (Tm4/S.2) and mutants (K1CB1, W2, Cs1-2 and V1/S) malaria parasites.

Abstract: The present invention is anti-folate antimalarials with dual-binding modes of the general formula (I) [refer to structure in the abstract] wherein R1 and R2 which may be the same or different are independently selected from methyl or ethyl or alkyl-phenyl, R3 is independently hydrogen, halide, lower alkyl substituted with ester, carboxylic, amide, and ether. Linker is X(CH2)nY wherein X and Y which may be the same or different are independently selected from oxygen, carbon, nitrogen, substituted phenyl where n is an integer from 1 to 2-6, or pharmaceutically acceptable salts therefore. The anti-folate antimalarials with dual-binding modes act as novel inhibitors with good inhibition constants against wild-type, double (C59R+SIOSN), triple (N51+C59R+SIOSN, C59R+S 1 OSN+I164L), and quadruple (N51+C59R+S108N+I164L) mutant enzymes. The compounds are also effective against wild type (Tm4/S.2) and mutants (K1CB1, W2, Cs1-2 and V1/S) malaria parasites.

Abstract: The present invention relates to novel compounds that are inhibitors of wild type and mutant dihydrofolate reductase (DHFR) of Plasmodium falciparum, which are useful for the treatment of malaria. It also relates to processes of making and using such compounds. The antimalarial compounds of the present invention have low toxicity to a host infected with the malarial parasite, and are potent when administered in pharmaceutical compositions.

Abstract: The present invention relates to novel compounds that are inhibitors of wild type and mutant dihydrofolate reductase (DHFR) of Plasmodium falciparum, which are useful for the treatment of malaria. It also relates to processes of making and using such compounds. The antimalarial compounds of the present invention have low toxicity to a host infected with the malarial parasite, and are potent when administered in pharmaceutical compositions.

Abstract: Compounds of the formula (I) wherein R1 represents a hydrogen atom or a 3-halogen atom, and R2 represents a straight-chain alkyl group containing up to 6 carbon atoms, a straight-chain alkyl group containing up to 3 carbon atoms with unsubstituted or substituted aromatic ring, or alkoxycarbonyl substituent at the end position, or aryloxyalkoxyalkyl group have been found to possess antimalarial activity against Plasmodium falciparum lines, including those resistant against pyrimethamine and other antifolates. The compounds themselves, methods of making these compounds, and methods of using these compounds are all disclosed.

Abstract: Compounds of the formula (I) wherein R1 represents a hydrogen atom or a 3-halogen atom, and R2 represents a straight-chain alkyl group containing up to 6 carbon atoms, a straight-chain alkyl group containing up to 3 carbon atoms with unsubstituted or substituted aromatic ring, or alkoxycarbonyl substituent at the end position, or aryloxyalkoxyalkyl group have been found to possess antimalarial activity against Plasmodium falciparum lines, including those resistant against pyrimethamine and other antifolates. The compounds themselves, methods of making these compounds, and methods of using these compounds are all disclosed.