Diaminopyrimidine potentiators

Fig. 3.7 Chemical structures of commonly used sulfonamides and diaminopyrimidine potentiators.

Extraction of sulfonamides and diaminopyrimidine potentiators from edible animal products should render the bound residues soluble, remove most or all of the proteins, and provide high yields for all analytes. Sample extraction/deprotei-nization is traditionally accomplished with polar solvents including acidic aqueous solutions (211,214-222), acetonitrile (56,223-232), chloroform (233-240), ethyl acetate (29,241-244), dichloromethane (204,242,245-247), acetone (194, 248, 249), or various combinations of them. Use of dichloromethane at pH 10 in the presence of an ion-pairing reagent (tetrabutylammonium) has also been reported to work extremely well in the extraction of sulfadimethoxine and ormeto-prim residues from catfish muscle (250) and animal tissues (251). Anhydrous sodium sulfate may be added to dehydrate tissue samples to permit better exposure of the matrix to tire solvent. 

Liquid-liquid partitioning has been used for many years for Ure purification of sulfonamides and diaminopyrimidine potentiators. When partitioning from an organic into an aqueous phase, the adjustment of the pH of Ure aqueous phase is critical to obtain quantitative recoveries.. Sulfonamides are generally extracted from Ure primary organic sample extract into strong acidic (238, 239, 242, 249, 252-254) or basic (241, 248, 255) aqueous solutions. For better sample cleanup, back-extraction of Ure analyte(s) into dichloromethane (241, 253, 254), or ethyl acetate (256), after pH adjustment of the aqueous phase at values between 5.1... 

Following their extraction and cleanup, residues of sulfonamides and diaminopyrimidine potentiators in sample extracts can be detected by direct nonchro-matographic methods, or thin-layer, gas, liquid, or supercritical fluid chromatographic methods (Table 29.7). 

Physicochemical Methods for Sulfonamides and Diaminopyrimidine Potentiators in Edible Animal... 

Because 5-nitrosopyrimidines are so accessible, their oxidation to the corresponding nitropyrimidines is of considerable potential use. Thus, 4,6-diaminopyrimidin-2(l//)-one... 

Similarly, Dang and co-workers reported the displacement of one chloride from pyrimidine 44 with various amines to give diaminopyrimidines 45 <00TL6559>. These compounds were then subjected to a FeCb-SiOz-promoted cyclocondensation with various aldehydes to produce trisubstituted purines 46 in moderate to good yields as potential adenosine regulating agents. 

Trimethoprim is a diaminopyrimidine derivative. It is reasonably basic (p/fa 7.2) and we should remember here that amino substituents are able to utilize their lone pairs and provide resonance stabilization to a conjugate acid. Consequently, aminopyrimidines protonate on a ring nitrogen. If we consider protonation of the two ring nitrogens separately, and then think about potential resonance stabilization, we can predict the site of protonation. 

Pyrimethamine (Daraprim) is the best of a number of 2,4-diaminopyrimidines that were synthesized as potential antimalarial and antibacterial compounds. Trimethoprim (Proloprim) is a closely related compound. 

The sulfonamides are a group of organic compounds with chemotherapeutic activity they are antimicrobial agents and not antibiotics. They have a common chemical nucleus that is closely related to PABA, an essential component in the folic acid pathway of nucleic acid synthesis. The sulfonamides are synergistic with the diaminopyrim-idines, which inhibit an essential step further along the folate pathway. The combination of a sulfonamide and a diaminopyrimidine is advantageous because it is relatively non-toxic to mammalian cells (less sulfonamide is administered) and is less likely to select for resistant bacteria. Only these so-called potentiated sulfonamides are used in equine medicine. These drugs are formulated in a ratio of one part diaminopyrimidine to five parts sulfonamide, but the optimal antimicrobial ratio at the tissue level is 1 20, which is achieved because the diaminopyrimidines are excreted more rapidly than the sulfonamides. 

Resistance to the diaminopyrimidines usually occurs by plasmid-encoded production of diaminopyrimidine-resistant DHFR. Excessive bacterial production of DHFR and a reduction in the ability of the drug to penetrate the bacterial cell wall also results in resistance. There is less resistance to the potentiated sulfonamides than to the individual agents. 

In the following example, QSAR was useful not only in determining the stmcture of a potentially active drug but also in determining something about the stmcture of the receptor site. A series of substituted 2,4-diaminopyrimidines, used as inhibitors of dihydrofolate reductase (Section 25.8), was investigated. 

The sulfonamide class contains a large number of antibacterial drugs, including sulfadiazine, sulfamethazine (sulfadimidine), sulfathiazole, sulfamethoxazole, and many more. Potentiated sulfonamides, in which a sulfonamide and an antibacterial diaminopyrimidine such as trimethoprim are combined, demonstrate improved efficacy compared with sulfonamides alone. Relatively few sulfonamides are currently (as of 2011) approved for use in food-producing species. This is attributed to numerous factors, including toxicological concerns associated with some sulfonamides and the lack of contemporary data to support the historical uses of other sulfonamides. 

Despite potentially interesting molecular recognition, agrochemical and medicinal properties, the syntheses of 6-aryl-2,4-diaminopyrimidines and triazines are largely unexplored. Recently, Cooke et al. have described the high yielding synthesis of such compounds via palladium-catalyzed Suzuki coupling reactions of commercially available 6-chroro-2,4-diaminopyrimidine (10) or 6-chloro-2,4-diaminotriazine (11) and aryl boronic acids (Equations 24 and 25) (27). 

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