Sulfonamides systemic antibacterials

Two distinct approaches can be envisioned in the development of siderophore-drug conjugates. A strategy of drug delivery utilizing the pathogen s own iron-transport system to act as a delivery system has been referred to as the Trojan Horse approach. Examples in which sulfonamides 194 , penicillins, cephalosporins and other antibiotics attached to DFO which exhibit antibacterial activity were reported. 

The development of sulfonamide carbonic anhydrase inhibitors was based on the observation that antibacterial sulfanilamides produce alkaline urine. This discovery led to the development of acetazolamide (8.29), a thiadiazole derivative. It is not an ideal drug because it promotes K+ excretion and causes a very high urine pH. Since chloride ions are not excreted simultaneously, systemic acidosis also results. Much more useful are the chlorothiazide (8.30) derivatives, which are widely used as oral diuretic drugs. These compounds differ from one another mainly in the nature of the substituent on C3 ... 

Amines have occasionally been incorporated into an azo linkage to produce a prodrug. In fact, it was an azo dye. prontosil. (hat led to the discovery of the sulfonamides as the first antibacterials to be used to treat. systemic infections.--Although prontosil itself was inactive in vitro, it was active... 

Folic acid is a pteridine derivative (rings A and B constitute the pteridine heterocyclic system) synthesized by bacteria from GTP, p-aminobenzoic acid, and glutamic acid. Accordingly. the structure of folic acid is compased of three moieties the pteridine moiety derived from GTP. the p-aminobcnzoic acid moiety, and the glutamic acid moiety. (Antibacterial sulfonamides [see Chapter 8 compete with p-aminobenzoic acid and, thereby, interfere with bacterial folic acid synthesis.) Humans cannot synthesize folic acid. 

The sulfonamide drugs were the first effective antibacterial agents to be employed systemically in humans. These drugs resemble p-aminobenzoic acid in structure and inhibit utilization of that compound for the synthesis of folate in bacteria. Sulfonamides do not interfere with human metabolism. 

A typical use of PCA is illustrated by an example from antibacterial research. The antibacterial effects of sulfones and sulfonamides in whole-cell and cell-free systems has been analyzed. In this example, some missing activity data (19%) have been estimated by an iterative process using PCA. However, estimation of missing values should be done with care and preferably avoided. 

Coats, E. A., Cordes, H.-R, Kulkarni, V. M., Richter, M., Schaper, K.-J., Wiese, M., Seydel, J. K. Multiple regression and principal component analysis of antibacterial activities of sulfones and sulfonamides in whole cell and cell-free systems of various DDS... 

After systemic administration, sulfadiazine and sulfisoxazole attain concentrations in cerebrospinal fluid (CSF) that may be effective in meningitis. Sulfonamides readily cross the placenta to reach the fetal circulation, potentially exerting both antibacterial and toxic effects. 

Some dru used in the treatment of UTIs do not belong to the antibiotic or sulfonamide groups of dru. The dru discussed in this ch iter are anti-infectives (gainst infection) used in the treatment of UTIs, which have an effect on bacteria in the urinary tract. Although administered systemically, that is, by tlie oral or parenteral route, they do not achieve significant levels in tlie bloodstream and are of no value in tlie treatment of systemic infections. They are primarily excreted by the kidneys and exert their major antibacterial effects in tlie urine. (See Summary Drug Table Urinary Anti-infectives for a listing of tliese and other dru used to treat problems associated with the urinary system.)... 

The same inheritance controls the acetylation (deactivation) of the antibacterial sulfonamides, the anti-arrhythmic cardiac drug, procainamide (7.56) (Woosley et aL, 1978), the blood-pressure-lowering drug, hydralazine 11.47), and the amine derived by metabolism of the sedative, nitrazepam (12.98). In each case, rapid acetylation reduces the effect of the drug, but slow acetylators of hydralazine are unfortunate for they are prone to develop systemic lupus erythematosis, with arthritis-like symptoms (Batchelor a/., 1980). 

Similarly, a correlation was reported for the antibacterial activity of 15 groups of drugs acting in such diverse biological systems as intact animals. Isolated tissues, bacteria, etc. The authors excluded sulfonamides, which have a different from this correlation on the basis of... 

Miller, G.H., Doukas, P.H. and Seydel, J.K. 1972. Sulfonamide structure-activity relationship in a cell-free system. Correlation of inhibition of folate synthesis with antibacterial activity and physico-chemical parameters. J. Med. Chem. 15 700-706. 

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