Trimethoprim analogs

However, in the very end both projects failed with respect to drug design The Hb ligands do not permeate the erythrocyte membrane, and the trimethoprim analogs lost the high selectivity for bacterial DHFRs. 

Table 24. Trimethoprim analogs (23) as dihydrofolate reductase inhibitors [692]...

Diaveridine (1044) is a close relative of trimethoprim (Section 2.13.4.2.3) and is made by an analogous Principal Synthesis. It is used prophylactically against coccidiosis in poultry and in combination with sulfaquinoxaline as a curative agent for the same disease similar mixtures are also effective (64MI21305). 

The methylation of deoxyuridine monophosphate (dUMP) to thymidine monophosphate (TMP), catalyzed by thymidylate synthase, is essential for the synthesis of DNA. The one-carbon fragment of methy-lene-tetrahydrofolate is reduced to a methyl group with release of dihydrofolate, which is then reduced back to tetrahydrofolate by dihydrofolate reductase. Thymidylate synthase and dihydrofolate reductase are especially active in tissues with a high rate of cell division. Methotrexate, an analog of 10-methyl-tetrahydrofolate, inhibits dihydrofolate reductase and has been exploited as an anticancer drug. The dihydrofolate reductases of some bacteria and parasites differ from the human enzyme inhibitors of these enzymes can be used as antibacterial drugs, eg, trimethoprim, and anti-malarial drugs, eg, pyrimethamine. 

Another dihydrofolate inhibitor trimethoprim is an important antibacterial drug, usually given together with a sulfonamide. Although it is not as close a structural analog of folic acid as is methotrexate, it is... 

The conformations, as determined by crystal structure analyses, of 1-methylweberine, two tetramethoxy weberine analogs, and three polymetho-prims, shown in Fig. 16, are displayed in Figs. 18 and 19. These compounds were synthesized by Takahashi and Brossi (39a) and the crystal structures were determined by J. L. Flippen-Anderson, J. F. Chiang, and I. L. Karle (39b), with the exception of trimethoprim (40) where the three adjacent methoxy groups have the same conformation as shown in Fig. 17(c). 

Folate analogs such as trimethoprim have potent antibacterial and antiprotozoal activity. Trimethoprim binds lO -fold less tightly to mammalian dihydrofolate reductase than it does to reductases of susceptible microorganisms. Small differences in the active-site clefts of these enzymes account for its highly selective antimicrobial action. The combination of trimethoprim and sulfamethoxazole (an inhibitor of folate synthesis) is widely used to treat infections. 

Folate analogs such as trimethoprim have potent antibacterial and anti-... 

D. Bacteria must synthesize the folate that is required for their biosynthetic processes they do not have a transporter to bring folate into the cell. Trimethoprim inhibits prokaryotic DHFR (eukaryotic is not affected) and sulfamethoxazole is an analog of p-aminobenzoic acid (PABA), a precursor to folic acid. Bacteria will use this analog instead of PABA and produce a nonfunctional folate. 

Trimethoprim (TMP), a folate analog and inhibitor of dihydrofolate redudase (Figure V-l -3), is usually j... 

Kuyper et al. (208) modeled the binding of the bacterial DHFR-selective antibiotic trimethoprim (11 A) using the X-ray structure of the . coli-methotrexate complex. They assumed that the pyrimidine ring of trimethoprim would bind analogously to the corresponding pteridine ring of methotrexate (their model was later shown to be qualitatively correct by... 

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