Sulfanilamide derivatives

A monograph (1) covers the pioneering period of sulfa dmg development and describes over 5000 sulfanilamide derivatives, their preparation, properties, trade names, and biological testing. This review is remarkably complete through 1944. Several thousand additional derivatives have been made since, but no comparable coverage is available. A definitive account of medical appHcations up to 1960 has been pubHshed (2), and a review of experimental antibacterial aspects has been made (3). Chapters on general aspects of sulfonamides and sulfones have appeared (4,5). A review of the clinical efficacy of trimethoprim—sulfamethoxazole has been pubHshed (6). 

During the most active period of investigation of sulfanilamide derivatives, 1935—1944, for systemic bacterial infections, the antimycobacterial activity of 4,4 -dianainodiphenylsulfone [80-08-8] (DDS, dapsone) was discovered (14). Although neither this compound nor its derivatives proved to be clinically usehil for human tuberculosis, it did evolve into the most important type of compound for leprosy (15). The diacetyl derivative has also... 

Levulinic acid is fairly easily converted into thiazole derivatives by the intermediate formation of an a-halogenated ketone such as the /3-bromo derivative (XL) or /3-chloro derivative, which reacts with thiourea to form 2-amino-4-methyl-5-thiazoleacetic acid (XLI) or with thioformamide to give 4-methyl-5-thiazoleacetic acid (XLII). The aminothiazole (XLI) and its ethyl ester (XLIII) have been converted into their corresponding sulfanilamide derivatives, (XLIV) and (XLV). These sulfanilamides, particularly the acid XLIV, have considerable chemotherapeutic activity moreover the acid possesses distinct solubility advantages over sulfathiazole itself. 

Chlorination of the pyridazone yields 3rchloro-6-methyl-pyridazine (XLVIII) which on treatment with ammonia gives 3-amino-6-methyl-pyridazine (XLIX). The sulfanilamide derivative (L) has promising... 

Sulfanilamide derivatives of 5-membered heterocycles, solubility data 88MI54. 

Saccharin sodium is the oldest artificial sweetener. It is a sulfanilamide derivative and is stable within a wide range of temperatures but, in the presence of acids, does react chemically, and therefore is not compatible with preservatives that require low pH. In its acidic form, saccharin is not particularly water soluble. Therefore, the form used is usually the sodium salt. The calcium salt is also sometimes used, especially for restricting dietary sodium intake. Many studies have been carried out on saccharin, with some showing a correlation between saccharin consumption and increased cancer (especially bladder cancer) and others showing no such correlation. Nevertheless, no study has ever shown health risks in humans when saccharin is taken at normal doses. It has been approved for use in the USA but not in Canada, and was approved for use in Europe for children over 3 years of age. 

Replacing sulfa drugs (sulfanilamide derivatives) with novel chhydropter-oate synthase (DHPS) inhibitors 13FMC1331. 

Zhong, Z., Ji, X., Xing, R. et al. 2007. The preparation and antioxidant activity of the sulfanilamide derivatives of chitosan and chitosan sulfates. Bioorg. Med. Chem. Lett. 15 3775-3782. 

Outline a possible synthesis of the sulfanilamide derivative, 18, using benzene as the only source of an aromatic ring. Use any needed aliphatic or inorganic reagents. 

Currently the sulfa drugs are stUl very important therapeutic agents, but have to a large extent been replaced by antibiotics, such as the penicillins. Their low cost and general effectiveness for urinary tract infections, however, stiU make sulfanilamide derivatives attractive alternatives. These compounds have also found a valuable role in veterinary medicine. 

Sulfonamides are effective chemotherapeutics against coccus infections. The most effective sulfonamides include N -substituted derivatives of sulfanilamide. Derivatives of carbonic acid as well as heterocyclic rings usually serve as substituents. The other part of sulfanilic acid, H2N-QH4-SO2-, is abbreviated as sulfa . Consequently, the names of sulfonamides are composed of the prefix... 

The antagonism of bactericidal sulfanilamides by p-aminobenzoic acid (PABA), a precursor of the vitamin folic acid, has been well documented in the pharmacological literature. More recently, it was shown that the phytotoxic activity of asulam, a herbicidal sulfanilamide derivative, also results from an inhibition of the biosynthesis of the vitamin folic acid. " In particular, asulam inhibits competitively the enzyme 7,8-dihydropteroate synthase, which catalyzes the conversion of 2-amino-4-hydroxy-6-hydroxy-methyl-7,8-dihydropteridine and PABA to dihydropteroic acid, leading to folate depletion. A consequence of the depletion of folic acid derivatives is the buildup of intermediates of the de novo synthesis of purine nucleo-tides. ° Such intermediates include 5 -phosphoribosyl glycineamide (GAR) or 5 -phosphoribosyl-5-amino-4-imidazole (AICAR). The accumulation of GAR and AICAR in asulam-treated pea seedlings has been reported. 

Sulfonamides derived from sulfanilamide (p-arninoben2enesulfonainide) are commonly referred to as sulfa dmgs. Although several dmg classes are characterized by the presence of a sulfonamide function, eg, hypoglycemics, carbonic anhydrase inhibitors, saluretics, and tubular transport inhibitors, the antibacterial sulfonamides have become classified as the sulfa dmgs. Therapeutically active derivatives are usually substituted on the N nitrogen the position is generally unsubstituted. These features are illustrated by the stmctures of sulfanilamide (1) and sulfadiazine (2)... 

In a few cases, A/ -heterocycHc sulfanilamides have been prepared by the condensation of an active heterocycHc haHde with the sulfonamide nitrogen of sulfanilamide or its A/-acetyl derivative in the presence of an acid-binding agent. Sulfapyridine, sulfadiazine, and sulfapyrazine have been made by this method (1), but the most important appHcation is probably for the synthesis of sulfachlorapyridazine (9) and sulfamethoxypyridazine (10) (45). 

The first pyrimidine analogues of sulfanilamide were introduced in 1942, some five years after the start of the bacterial chemotherapy revolution. Sulfadiazine (1018 R = R = H) and sulfamerazine (1018 R = Me, R = H) may be made by treatment of pyrimidin-2-amine or its 4-methyl derivative, either with p-acetamidobenzenesulfonyl chloride followed by... 

It is often advantageous to proceed to a desired product through two nucleophilic displacements rather than directly when one can exploit a difference in the reactivity of two leaving groups. An example is the conversion of 4-chloro-2,6-dimethoxypyrimidine (109) (not satisfactorily reactive with sulfanilamide anion) by means of trimethylamine into the more reactive trimethylammonio derivative 110. Conversion of chloro-quinohnes and -pyrimi-dines into nitriles is best accomplished by conversion (with sulfite) into the sulfonic acids before reaction with cyanide. 

Aryloxy, hydroxy arylsulfonyloxy, and phosphoryloxy. The 4-toluenesulfonyloxy and 4-nitrophenyloxy groups approximate the chloro group in replaceability in benzene derivatives. The former appears to be less reactive than chloro toward hydroxide on quinoline and -phenoxy on pyrimidine is relatively unreactive toward sulfanilamide anion or ammonia. On cinnoline, quinazoline, or quinoline, a 4-phenoxy group is less reactive than a chloro group. 

A sulfanilamide drug of prolonged action, 2-p-aminobenzenesulfamido-4-methylpyiimidine (sulfomerazine 162), first prepared by Japanese chemists from acetacetic aldehyde in 82% yield (49JPJ447), ranks among practically valuable 2-amino-4-methylpyrimidine derivatives. Later, a synthesis of this product directly from l-methoxybut-l-en-3-yne (100°C, AcONa, AcOH, 3 h) in 64% yield has been developed (76MI1). 

Dihydropteroic acid (85) is an intermediate to the formation of the folic acid necessary for intermediary metabolism in both bacteria and man. In bacteria this intermediate is produced by enzymatic condensation of the pteridine, 86, with para-amino-benzoic acid (87). It has been shown convincingly that sulfanilamide and its various derivatives act as a false substrate in place of the enzymatic reaction that is, the sulfonamide blocks the reaction by occupying the site intended for the benzoic acid. The lack of folic acid then results in the death of the microorganism. Mammals, on the other hand, cannot synthesize folic acid instead, this compound must be ingested preformed in the form of a vitamin. Inhibition of the reaction to form folic acid Ls thus without effect on these higher organisms. 

N1 -acylsulfanilamides, 23 508 A21-heterocyclic derivatives, 23 508 Ar -heterocyclic-Ar -acylsulfanilamides, 23 508 A21-heterocyclic sulfanilamides, 23 507—508 2V-(2-aminoethyl)-l,3-propylenediamine physical properties, 5 486t 2V-(2-aminoethyl)-piperazine (AEP), 5 485 N2 oxidation, Birkeland-Eyde process of, 27 291-292, 316. See also Dinitrogen entries Nitrogen entries N3 -P5 phosphoramidates, 27 630-631 Na+, detection in blood, 24 54. See also Sodium entries Nabarro-Herring creep, 5 626 Nacol 18, chain length and linearity, 2 10t Nacreous pigments, 7 836-837 19 412 Nacrite, 6 659... 

Two of these systems were studied as models—the acetylation of choline in brain to give acetyl choline (Hebb, Nachmansohn), and of sulfanilamide (the active component in prontosil, Chapter 3) in liver (Lipmann). Sulfanilamide is rapidly inactivated by acetylation on the p-amino group and then excreted. Sulfanilamide is easily diazotized the diazonium salt formed can be coupled with N-( 1 -naphthyl)ethylenedi-amine dihydrochloride to give a pink derivative (Bratton and Marshall, 1939). This formed the basis for an elegant colorimetric assay. Only the free p-amino group reacts, so that as acetylation proceeded color formation diminished. 

The nitrite ions are detected by the Griess reaction, starting with their reaction with an aniline derivative, such as sulfanilic acid, or sulfanilamide. The reaction is carried out in an acidic medium (e.g., acetic acid) and leads to the formation of a diazonium ion (Eq. (8)) ... 

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