Active sulfonamides

Topically active sulfonamides are useful in preventing infections in burn patients. Mafenide acetate... 

In summary, with the novel reactions described, the door was opened to a rich new chemistry of optically active sulfonamides, sulfonates, and sultones. 

The physiologically active sulfonamide (sulfa) drugs involve variations of groups in place of the hydrogen of the sulfonamide moiety. 

Optically active (S, S)-121 gave the optically active sulfonamide 164b in 94% enantiomeric purity with overall retention of configuration at the allylic a-carbon.79... 

Rivaroxaban (BAY 59-7939) <2005JME5900> is an oral anticoagulant currently under development. It acts by inhibiting the active form of coagulation factor Xa. Sitaxentan <2004JME1969, 2005MI985> is an orally active sulfonamide class endothelin-A receptor antagonist. 

For the drug to be antibacterially effective, however, the active sulfonamide must be liberated by deconjugation and the transport-restricting moiety must be disposable. In the intestinal contents slow hydrolysis of the sulfonamide conjugates takes place, thus ensuring effective concentrations of the active antibacterial agent in the lower parts of the intestinal tract. 

M. I. Ayad, A. Mashaly, and M. M. Ayad, Thermal behaviour and electrical properties of some biologically active sulfonamide Schiff bases, Thermochim. Acta 184, 173-182 (1991). 

Table 6. Toxicity of Some Miscellaneous to Fire Ant Workers Active Sulfonamides ...

AM toxin, 151 Acetylenic ketone, 148 Active sulfonamides, 234 Aedes aegypti L., 275 Agrochemicals historical view, 1 side effects, 2 Alectra orobanchoides, 448 Alectra vogelii, 448 Aliphatic alcohol-substituted sulfonamides, 232... 

This also applies for protonations with optically active sulfonamides as the proton source (see table below)159. Whereas the highest selectivity (46% ee) is achieved with an (f ,f )-bissulfon-amide160, the lowest ee (5%) is obtained when the 4-methylphenylsulfonyl moiety is coupled to (S)-ethyl phenylalaninate. In the latter case, the highest ee (40%) is obtained when the (S)-alaninate is coupled with the (S)-camphorsulfonyl group. The stereogenicity of the cam-phorsulfonyl moiety is even more significant since its combination with the (/ )-alaninate still yields the (S)-lactone in 18% ee. 

Although lipid solubility at physiological pH enhances a drug s penetrability of a membrane, too much may not necessarily result in increased activity. Many antibacterial sulfonamides exhibit their peak effectiveness at pH values at which they are only approximately half-ionized. These sulfonamides have pKa values in the 6-8 range. The apparent reason is that even though the molecular form can readily penetrate the bacterial membrane, only the anionic form is bacteriostatic once inside. Thus approximately 50% ionization appears to be optimal. Nevertheless, several highly active sulfonamides exist with a pKa considerably outside of this optimal range. Other factors are also presumably involved. 

In order to counteract resistance development and to improve antibacterial activity, sulfonamides are typically combined with an inhibitor of dihydrofolate reductase (Figure 2, i). Dihydrofolate reductase is a core enzyme of human central intermediary metabolism. Although the bacterial and mammalian dihydrofolate reductases are orthologues with considerable sequence similarity, trimethoprim (35) has sufficient selectivity to enable the selective inhibition of the parasite enzyme. 

Seydel (1966) has shown that there is an approximate linear relationship between Hammett <7-values for various benzeneamines (related to the sulfonamides) and the logarithm of the lowest concentration of a sulfa drug to show inhibition of bacterial growth. The more positive the Hammett ortho-halogenated amine, which proved to give a more active sulfonamide than could be expected from its Hammett [Pg.403]

Activated sulfonamides and other activated amines were used in a series of Mitsunobu reactions to prepare analogs of 2-(sulfanamido)methyl carbapenems (124) as potential anti-MRSA compounds. The basic reaction scheme and some of the activated amines that were used are shown in the figure below. Additional examples can be found in the original paper. 

Montero et al. employed the TPP/DIAD and TBP/ADDP redox couples to prepare the Mitsunobu betaine as a base under mild conditions Deprotonation of the doubly activated sulfonamide 239 then produced die reactive anion that was alkylated in situ by a variety of alkyl bromides (benzyl, allyl, a-acetobromoglucose, etc.). Attempts to prepare the alkylated products via more traditional mineral base conditions using sodium or potassium carbonate gave much inferior yields of around 10%. The TBP/ADDP couple, as shown below, gave better yields in the alkylation chemistry generally, the modest alkylation yields are around 40-60%. 

Preparation of para-acetylaminobenzensulfonyl chloride (PAS) was described in Example 7.2. Sulfonation of 2-aminothiazole is performed in aqueous medium under controlled addition of hydroxide according to the already-discussed Schotten-Baumann process. As the result, double-sulfonated amine is formed, which does not represent a serious technological issue since on heating with ammonia to the reaction pot, selective ammonolysis is achieved and one mole of sulfonamide obtained. This is a useful side product that on separation is recycled in the production of biologically active sulfonamides. The ammonium salt of the sulfathiazole precursor is submitted to hydrolysis of the A-acetyl group and sulfathiazole isolated by crystallization. 

Kaw cki used optically active sulfonamide 234 to perform an asymmetric aza-Diels-Alder reaction with Rawal diene 235. " The reaction was performed in the presence of a Lewis acid, trimethylsilyl trifluoromethanesulfonate (TMSOTf), to obtain dihydropyridinone 236 as the product with high enantiomeric excess (Scheme 40.51). 

Astwood, Sullivan, Bissell, and Tyslowitz (90) reported very similar results and reached somewhat similar conclusions. These investigators found sulfadiazine to be by far the most active sulfonamide tested although less active than thiourea. They postulated that a single hypophyseal factor is concerned with both hyperplasia and oversecretion of the thyroid, The sequence of events they consider to be as follows First, inability of the organism to synthesize thyroid hormone at a normal rate, with consequent reduction in the amount of circulating hormone second, a resultant production of excess thyrotropin by the pituitary which stimulates the thyroid to hyperplasia and to the release of the thyroid hormone stored therein and, third, a reduction of the BMR due to exhaustion of the stored thyroid hormone plus reduction in its rate of synthesis. 

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