Derivatives of p-aminobenzoic acid and their action on the growth of bacteria
SummaryVarious derivatives of P.A.B. obtained by introduction of substituents in the benzene-nucleus have been examined for their action on the growth ofAerobacter aerogenes in a simple synthetic medium and ofDiplococcus pneumoniae in ascites-broth without peptone.The following results have been obtained:1.The 2-amino, 3-amino, 3-chloro, 3-bromo, 2-methyl, 3-methyl, and 2.3-dimethyl derivatives of P.A.B., and also 2-sulfanilamido-4-aminobenzoic acid have sulfonamide activity.2.The 2-hydroxy, 2-fluoro, and 2-nitro derivatives have an antisulfonamide activity similar to the activity of P.A.B., although weaker.3.The 3-hydroxy, 2-chloro, and 2-bromo derivatives show sulfonamide-activity in relatively high concentrations. In lower concentrations they act as anti-sulfonamides.4.The 3-nitro, 2.6-dimethyl, and 3.5-dimethyl derivatives, and methyl 2-acetamino-4-amino-benzoate are completely inactive. These results have been compared with those of other investigators and the causes of some contradictions have been elucidated.
THE ANTIBACTERIAL ACTION OF DERIVATIVES AND ANALOGUES OF p-AMINOBENZOIC ACID
The bacteriostasis induced by the sulfonamide drugs is reversed by p-aminobenxoic acid (PAB) in appropriate concentrations (1). It is now well established that PAB is a normal constituent of cells (2) and that the bacteriostatic effects of the sulfonamides are explicable in terms of their structural similarity to PAB (3). The precise rble of PAB in cellular metabolism has yet to be clarified but whether it functions as a substrate as some investigators postulate (4), or more likely as a prosthetic group; clearly it must be involved in some reaction which is vital to the growth of many microorganisms. The sulfonamides, presumably by competing with PAB for a part in this key reaction, are able thereby to disrupt the economy of certain growing cells. Assuming that PAB is the molecule to be imitated, it follows that there must be compounds other than the sulfonamides which can compete with PAB. Thus, for example, sulfur-free compounds related in structure to PAB might be expected to produce bacteriostatic effects comparable to those of the sulfonamides. When the chemotherapeutic possibilities of derivatives and analogues of PAB were investigated, two objectives were in mind: (1) to develop another line of evidence in support of the thesis that the resemblance of the sulfonamides to PAB is the basis of their bacteriostatic properties and (2) to determine whether the bacteriostatic potencies reached by sulfonamides could be duplicated in other molecular configurations and whether the toxic properties which accompany the bacteriostatic effects of the sulfonamides would apply as well to other such bacteriostatic compounds. When the present investigation was begun, it had been reported that p-nitrobeneoic acid arrested quite strongly the growth of certain bacteria (5). Subsequently, Hirsch (6) showed that p-aminobenzamide also possessed bacteriostatic properties. While the work here described was in progress, Auhagen (7) and Kuhn and coworkers (8) reported varying degrees of antibacterial action for several sulfur-free compounds related
Determination of iodide with 1,3-dibromo-5,5-dimethylhydantoin (DBH) in comparison with the ICl-method. Analytical methods of pharmacopeias with DBH in respect to environmental and economical concern. Part 3.
USP 1995 (The United States Pharmacopeia, 23rd Edit., (1995), potassium iodide p. 1265, sodium iodide p. 1424), PH. EUR. 1997 (European Pharmacopoeia, third ed., Council of Europe, Strasbourg, (1997), potassium iodide p. 1367, sodium iodide p. 1493) and JAP 1996 (The Japanes Pharmacopoeia, 13th ed. (1996), potassium iodide p. 578, sodium iodide p. 630) determine iodide with the ICl-method (J. Am. Chem. Soc. 25 (1903) 756-761; Z. Anorg. Chem. 36 (1903) 76-83; Fresenius Z. Anal. Chem. 106 (1936) 12-23; Arzneibuch-Kommentar, Wissenschaftliche Erläuterungen zum Europäischen Arzneibuch, Wissenschaftliche Verlagsgesellschaft mbH, Stuttgart, Govi-Verlag - Pharmazeutischer Verlag GmbH, Eschborn, 12th suppl. (1999), K10 p. 2), using chloroform, which is toxic and hazardous to environment. Without the application of chlorinated hydrocarbons USP 2000 (The United State Pharmacopeia, 24th ed. (2000), potassium iodide p. 1368, sodium iodide p. 1535) and Brit 1999 (British Pharmacopoeia London, (1999), Appendix VIII C, p. A162) titrate iodide with the redox indicator amaranth. A titration with potentiometric indication giving two end-points at the step of I(2) and [ICl(2)](-) is described. Due to the high concentration of hydrochloric acid required for the ICl-method, the determination with DBH (1,3-dibromo-5,5-dimethylhydantoin; 1,3-dibromo-5,5-dimethyl-2,4-imidazolidinedione) can be recommended and is performed easily. Similarly, the iodide content of gallamine triethiodide may be analyzed with DBH by application of a visual two-phase titration in water and ethyl acetate or with potentiometric indication in a mixture of 2-propanol and water. During the removal of the excess of DBH 4-bromo-triethylgallamine (2,2',2"-[1-bromo-benzene-2,3,4-triyltris(oxy)]N,N,N-triethylethanium) is formed.