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Category: Bacterial Pathogenesis
Dihydrofolate Reductase Inhibitors, Nitroheterocycles (Furans), and 8-Hydroxyquinolines, Page 1 of 2
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This chapter talks about dihydrofolate reductase inhibitors (DHFR), nitroheterocycles (furans), and 8-hydroxyquinolines. Trimethoprim and brodimoprim contain two nitrogen atoms on the pyrimidine ring which are easily protonable according to the pH of environment. Co-trimoxazole is one of the main antibacterial agents for the treatment of uncomplicated cystitis. Pharmacology studies show that the combination of compounds does not modify their behavior and that if co-trimoxazole is compared with the other combinations an advantage may be found for trimethoprim-sulfadiazine in urinary tract infections and renal insufficiency. Many 6-6 fused rings have been prepared with the aim of increasing the selectivity for T. gondii and P. carinii DHFR. A series of hybrids was synthesized. Within this series one analog was 500-fold more potent than trimethoprim against P. carinii and T. gondii and displayed an excellent selectivity. The combination of epiroprim and dapsone is highly effective against P. carinii pneumonia in rats and T. gondii infection in mice. In vitro, the sulfones are active against T. gondii, particularly dapsone. In murine P. carinii pneumocystosis, dapsone is effective in treatment and prevention. In humans, the combination trimethoprim-dapsone in curative treatment and dapsone alone in preventive treatment are effective. Like the sulfonamides, the sulfones interfere with folate synthesis. They also have a potent antioxidant action. Lastly, dapsone inhibits the transport of adenosine through the erythrocyte wall and prevents its incorporation in the nucleic acid of plasmodia and probably toxoplasmas and P. carinii.
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Sulfonamides for systemic use
Sulfonamides for intestinal use
N 4-acetylation of sulfonamides. Acetyl CoA, acetyl coenzyme A
Pyrimidine and pyridine sulfonamides: structures of hydroxy metabolites
2, 5-Diaminopyrimidine derivatives
Protonation and deprotonation of trimethoprim
Reduction to tetrahydrofolate
Mode of action of trimethoprim
Role of tetrahydrofolates and sites of action of sulfonamides and benzylpyrimidines
Mode of action of 2,4-diaminopyrimidines
Thymidylate activity
Degradation products of trimethoprim
2,4-Diaminobenzylpyrimidines with antiparasitic activities
Iclaprim
Enantiomers of AR-101
Compound A. TMP, trimethoprim
Sulfones
Nitroheterocycle furans
8-Hydroxyquinoline derivatives
Pharmacokinetics of sulfonamides
Solubilities of sulfonamides at 25ºC
Half-lives of sulfonamides in children
Tissue diffusion of sulfonamides and trimethoprim
Percentage of the sulfonamide administered dose eliminated unchanged or as metabolites in urine
Affinity for DHFR
ThyX and FolA gene distribution
Physicochemical properties of 2,4-diaminopyrimidines
In vitro activities of trimethoprim and brodimoprim against gram-positive cocci
In vitro activities of benzylpyrimidines against gram-negative bacilli
In vitro activity against S. maltophilia
Breakpoints (French Committee for Antibiotic Susceptibility Testing)
Prevalence of co-trimoxazole resistance
Prevalence of resistance of E. coli in urinary tract infections in France
In vitro activities of trimethoprim and co-trimoxazole
Comparative in vitro activities of trimethoprim and tetroxoprim
Affinities for DHFR of trimethoprim and piritrexin
Pharmacokinetic characteristics of the different benzylpyrimidine derivatives
In vitro activity of iclaprim
Affinity for DHFR of gram-positive cocci
Preliminary pharmacokinetics of iclaprim
Proprietary names of combinations
Plasma protein binding
Penetration in bronchial secretions
Trimethoprim distribution in blister fluid
2,4-Diaminopyrimidine systems for parasites
In vitro activity of epiroprim
In vitro activity of epiroprim against mycobacteria
In vivo efficacy of epiroprim
Physicochemical properties of sulfones
Dapsone slow and rapid acetylators (100-mg single oral dose to nine patients)