Sulfones, antibacterials

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). 

More recently, screening efforts at Novartis have identified a hydroxamic acid containing a benzothiazinone ring system (32) [108]. This inhibitor is very potent versus S. aureus Ni -PDF (<5nM) and displays good selectivity versus matrix metalloprotease-2 (MMP-2) and MMP-13. Unfortunately (32), and all other analogues prepared, such as carbon isosteres (33), sulfones (34), N-substituted analogues (35) and N-formyl-N-hydroxylamines (36), lacked appreciable antibacterial activity in spite of their potent enzyme inhibitory activity. Further studies performed by Novartis suggest that these molecules are unable to penetrate the outer cell membrane of E. coli, and may bind to the cell membrane of S. aureus [108]. 

Until the development of the antibacterial sulfones, Hanson s Disease (leprosy) remained a potentially horrible affliction, treated with largely ineffective ancient remedies. The antibacterial sulfonamides do not do well against this disease and, interestingly, the, sulfones which are effective, are not very useful... 

The antibacterial agent flumequine 280 was synthetized in optically active form by starting with resolution of the two enantiomers of a suitably substituted racemic tetrahydroquinoline through formation of the (lf )-3-bromocamphor-8-sulfonates. After N-alkylation of the (2K)-tetrahydroisoquinoline enantiomer 277 with diethyl ethoxymethylene-malonate to give 278, the quinolizidine system 279 was formed by acylation onto the peri-position. This compound was finally hydrolyzed to afford 280 (Scheme 60) <1999TA1079>. 

Antibacterial sulfones, 23. 493 Antiberiberi factor, 25 781 Antibiotic peptides, 13 252-253. See also Antimicrobial peptides synthesis of, 13 254 Antibiotic resistance, 3 23—40 biochemical strategies, 3 30-38 molecular targets for antibiotics,... 

Antibacterial sulfonamides contain two N-atoms, the sulfonamido (N1) and the para primary amino (N4). The sulfonamido group, in contrast to a carboxamido group, is chemically and metabolically stable. In other words, hydrolytic cleavage of sulfonamides to produce a sulfonic acid and an amine has never been observed. We, therefore, focus our discussion on the primary amino group, acetylation of which is one of the major metabolic pathways for some sulfonamides. Hydrolysis of the N4-acety luted metabolites back to the parent sulfonamide can occur in the liver, kidney, and intestinal tract. The reaction is strongly influenced by the structure of the parent amine e.g., N4-acetylsulfisoxazole (4.121) was deacetylated by intestinal bacteria whereas /V4-acctyIsulI anilamide (4.122) under identical conditions was not [78][79],... 

Twenty-five dibenzothiophenes, composed mainly of amino and acetamidodibenzothiophenes and their sulfoxides and sulfones, have been tested for antibacterial activity against Staphylococcus aureus, Escherichia coli, and Mycobacterium tuberculosis. Activity was found against the latter with 2- and 3-aminodibenzothiophene in synthetic culture media, but the effect was reversed by the addition of serum. " ... 

Clavulanic acid is isolated from Streptomyces clavuligerus [60-66], and sulbactam, a sulfone of penicillanic acid, is synthesized from 6-APA [67-69], Both compounds have extremely weak antibacterial properties and act by forming irreversible complexes with beta-lactamase, which inactivates the enzyme, and as a result the beta-lactam antibiotic has time to destroy the microorganism. Currently, a number of combined drugs containing various combinations of beta-lactamase antibiotics and inhibitors are used. 

Inhibitors of P-lactamase are known. The synthetic sulfone tazobactam (9.38), and clavulanic acid (9.39) both have weak antibacterial activity besides P-lactamase inhibitory activity, and they can be used in combination with vulnerable antibiotics. 

These agents would be used as adjuncts to beta lactams since they have no antibacterial activity in their own right. A key reaction in the synthesis of each compound involves the replacement of the amine at 6 and the protection of that position as a mono- or di-halide. Thus reaction of 6-APA (2-4) with nitrous acid gives the diazonium salt (9-1) this is converted to the dibromide (9-2) on treatment with bromine. The ring sulfur is then oxidized with permanganate to the sulfone (9-3). Hydrogenolysis of the product replaces the two bromine atoms by hydrogen to afford sulbactam (9-4) [13]. 

Sulbactam is a penicillanic acid sulfone. It exhibits a weak antibacterial activity, and is an inhibitor of -lactamases produced by some bacteria. Hence, it can enhance the activity of penicillins and cephalosporins against many resistant organisms when used in combination with diese antibiotics. Sulbactam, although it has a spectrum similar to that of clavulanic acid, is, however, a less potent inhibitor. 

Penam Sulfone p-Lactamase Inhibitors. Natural product discoveries stimulated the rational design of /i-lactainase inhibitors based on the readily accessible penicillin nucleus. An early success was peni-cillanic acid sulfone, (2(5)-ru)-3,3-dimethyl-7-oxo-4,4-dioxide-4-thia-l-azabicyclo [3.2.0]heptane-2-carboxylic acid (sulbactam) (R = R1 = H,R2 = R = CH3), CsHnNOjS. The synthesis, microbiology, and clinical use of sulbactam have been reviewed. Sulbactam, with minor exceptions, is a weak antibacterial, but is a potent irreversible inactivator of many /3 lactamases, including penases and Richmond Sykes type 11, III, IV. V, and VI (Bactcroides) /3-lactamases. Sulbactam is better than clavulanic acid against type I Cephases, and synergy is observed for combinations of many penicillins and cephalosporins. Because sulbactam is not well absorbed orally, prodrug forms have been developed. Numerous other penicillin sul-fones have been reported to be /3-lactamase inhibitors. 

Alternatively, N-hyroxypyridine-2-thione, a versatile antibacterial and antifungal agent commercially available as Omadine, has been used. As expected, in the presence of DNA its photolysis causes SSBs (via OH), but after its photolytic consumption continuing photolysis at 350 nm caused the photooxidation of G in DNA and in dGuo (Adam et al. 1999). Apparently this effect is induced by one of its photolytic products that are largely the N,AT-dioxide, the mono-N-oxide, the disulfide and the sulfonic acid (Adam et al. 1999). 

Dapsone (Avlosulfon) is a member of a class of chemical agents known as the sulfones. Dapsone is especially effective against M. leprae and is used with rifampin as the primary method of treating leprosy. Dapsone appears to exert its antibacterial effects in a manner similar to that of the sulfonamide drugs that is, dapsone impairs folic acid synthesis by competing with PABA in bacterial cells. Primary adverse effects associated with dapsone include peripheral motor weakness, hypersensitivity reactions (skin rashes, itching), fever, and blood dyscrasias, such as hemolytic anemia. 

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