Sulfones antibacterial activity

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]. 

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. " ... 

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. 

The antibacterial activity and the toxicity of the disubsti-tuted sulfones are thought to be chiefly due to the formation in vivo of dap.sone. Hydrolysis of disubstituted derivatives to the parent sulfone apparently occurs readily in the acid medium of the stomach but only to a very limited extent following parenteral administration. Monosubstituted and nuclear-substituted derivatives are believed to act as entire molecules. 

Tazobactam, USP. Tazobactam is a penicillanic acid sulfone that is similar in structure to sulbactam. It is a nioK potent /3-lactamase inhibitor than sulbactam and ha.- 3 slightly broader spectrum of activity than clavulanic acid. Ii has very weak antibacterial activity. Tazobactam is available in fixed-dose, injectable combinations with piperacillin, a broad-spectrum penicillin consisting of an 8 I ratio of pipci- acillin sodium to tazobactam sodium by weight and ma-keted under the trade name Zosyn. The pharmacokineticsprotein bound, experience ven little metabolism, and are excreted in active forms in the urine in high concentrations. 

The antibacterial activity of monobactams has provided a great stimulus for synthetic work, and a large number of different compounds have been prepared.7 Sulfamic acid (86) can be used for sulfamation of fatty acid monoglycerides and other compounds. Reaction of aniline with hot sulfamic acid (170°C) afforded a mixture of sulfonic acids, namely orthanilic acid (99), sulfanilic acid (100) and the 2,4-disulfonic acid (101) (Scheme 43). 

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... 

The natural product squalamine and a model compound, both containing oligoammonium as well as sulfonate substituents, show antibacterial activity. They constitute ionophores, or possibly ion pore formers, and have been found to combine preferably with negatively charged phospholipid membranes of vesicles as compared to electroneutral ones (Scheme 3.5.2) (Deng et al., 1996 Fu-nasaki et al., 1990 Merritt et al., 1998). 

The poly-N-alkyl- and hexa-N-acyl derivatives of neomycin and paromomycin fail to show activity, but the hexa-N-methane-sulfonates and -sulfina-tes are claimed to be active and less toxic. 6 - and 6" -N alkyl- and N-alkylaryl-neomycins and -paromomycins have been prepared from the Schiffs bases by reduction with NaBH4 Some of the alkylaryl compounds show a slightly improved activity the alkyl derivatives are ineffective. The hexa-N-benzylneomydns prepared from neomycin, aromatic aldehydes and NaBH4, as well as the corresponding paromomycins, synthesized by means of catalytic reduction of the Schiffs bases, have reduced antibacterial activity. The Schiffs bases of paromomycin show in vitro the same activity as the parent compoimd, obviously because of the ease of hydrolysis. 

Methyl methacrylate (MMA) and sodium styrene sulfonate (SSNa) are water-soluble. These polymers behave like a low MW surfactant as they form micelles in aqueous solution in which the hydrophobic part is directed towards the centre and the hydrophilic part is situated on the periphery of the micelle. Owing to such features, amphiphilic block copolymers have wide-ranging applications in drugs, pharmaceuticals, coatings, cosmetics and paints. They also exhibit very high antibacterial activities. Oikonomou and co-workers used ATRP to prepare amphiphilic block copolymers, consisting of polymethyl methacrylate (PMMA) and poly (sodium styrene sulfonate) (PSSNa) blocks [18]. The synthesis methods are described below. 

Indole and its derivatives are found in many natural products as plant alkaloids that have antimicrobial [150], anti-inflammatory [151], antibacterial [152], and antidepressive activities. Many sulfur-containing compounds such as sulfates, sulfones, and sulfonomides exhibit insecticidal, germicidal, antimicrobial, and antibacterial activities [153,154] and certain phenyl sulfones show fungicidal properties [155]. 

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>. 

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