Structure activity relationship of penicillin and alcohol

structure activity relationship of penicillin and alcohol

See also Catecholamines. α, structural formula of, 96f α2 for muscle relaxation, theory and, 11 inverse, Agranulocytosis, antibiotic-induced, AIDS. 97 structural formula of, f structure-activity relationships of, 92t Alcohol(s). BACKGROUND OF THE INVENTION (A) Relation to cephalosporin antibiotic a chloroformate or bromoformate of the selected alcohol with the penicillin acid or .. Synthesis and structure-activity relationships in the cefpirome series. Structure-activity relationship of the antibiotic nucleotide-peptide microcin C51 . HPLC, beside peptaibols classically C-ended by a beta-amino alcohol.

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Furthermore, the activity of a compound against different strains of a bacterial species can vary. Nonetheless, there are certain trends and differences that can be observed. Muraymycin A1 is mainly active against Gram-positive bacteria such as S. Tunicamycin, capuramycin and FR only show antimicrobial activity against Gram-positive strains. This remarkable finding distinguishes the mureidomycins, pacidamycins, sansanmycins and napsamycins from other nucleoside antibiotics. On the other hand, caprazamycin B shows good activity against Gram-positive bacteria, Pseudomonas and M.

structure activity relationship of penicillin and alcohol

The related liposidomycins display good activity against M. Mode of action To develop an effective antibiotic one needs to choose a target that is essential for bacterial survival or growth and offers selectivity to strike only bacterial cells without cytotoxicity to human cells.

There are mainly four classical target processes for antibiotics: Novel approaches that differ from these established modes of action are under investigation, but many new compounds in development still address bacterial cell wall biosynthesis.

They are accompanied by a rich variety of prominent antibiotics in clinical use such as the penicillins [23,50,51]. While its thickness differs among bacteria — Gram-positive strains usually have a thicker cell wall relative to Gram-negative ones — the principle molecular structure remains identical: The exact composition of the peptide chain varies among different bacterial species.

It can be divided into three parts: Schematic representation of bacterial cell wall biosynthesis. The exact composition of the peptide chain varies in different organisms. This building block is then transported to the extracellular side of the membrane.

It is speculated that there might be some kind of 'flippase' involved but this particular step is still unclear and requires further investigation [55]. Both enzymes are members of the family of penicillin-binding proteins [23].

As mentioned above, there are many antibiotics in clinical use that target at least one step of bacterial cell wall biosynthesis. Prominent examples besides penicillins are cephalosporins, cycloserine, vancomycin, fosfomycin and daptomycin [9].

All of them except fosfomycin and cycloserine inhibit late, extracellular steps of cell wall formation. Thus, there are still many steps not addressed by clinically used drugs, which implies that cell wall biosynthesis still offers promising novel targets for the development of antibiotics with new modes of action.

Muraymycins and other nucleoside antibiotics target translocase I MraY that represents such a potential novel molecular target [22]. Overexpression of the mraY gene, identified in an mra murein region A cluster, led to an increase of UDP-N-acetylmuramoyl-pentapeptide: Gene knockout experiments revealed the MraY-catalysed reaction in cell wall biosynthesis to be an essential process for bacterial viability and growth [].

The cytosolic precursor UDP-MurNAc-pentapeptide is linked to undecaprenyl phosphate, a Cisoprenoid lipid carrier that is located in the cellular membrane.

With concomitant release of uridine monophosphate UMPthis furnishes a diphosphate linkage between the two substrates. The reaction is reversible and MraY accelerates the adjustment of the equilibrium state. Whereas this reaction was known for a long time [64,65]the structure of the MraY protein remained unclear. The mechanism of the MraY-catalysed reaction was investigated by kinetic studies by Heydanek, Neuhaus et al.

D.2 Penicillin mode of action (SL)

Proposed mechanisms for the MraY-catalysed reaction. Two-step mechanism postulated by Heydanek et al. Two-step mechanism postulated by Heydanek e Jump to Figure 6 The identification of the mraY gene [58] facilitated the alignment of MraY homologue sequences by van Heijenoort et al. Mutation of these three aspartate residues D, D and D in the E. This led to a proposed model for the active site of MraY in accordance with previous findings [66]: In a study with purified MraY from B.

They assumed that this would contradict the two-step mechanism as a nucleophilic residue is essential for the previously proposed mechanism. They found D98 to be crucial for activity and proposed its role to deprotonate undecaprenyl phosphate. InLee et al. MraYAA crystallised as a dimer and additional experiments showed that it also exists as a dimer in detergent micelles and membranes [71].

The previously proposed models are in agreement with the solved structure showing ten transmembrane helices and five cytoplasmic loops. The authors identified a cleft at the cytoplasmic side of the membrane that showed the highest conservation in sequence mapping.

Furthermore, it is also the region where most of the previously identified, functionally important residues [69] are located [71]. Surface calculation of MraYAA showed an inverted U-shaped groove that could harbour the undecaprenyl phosphate co-substrate. Nevertheless, there is still a need for further studies to fully understand the MraY-catalysed reaction at the molecular level [71]. In the context of a different MraY inhibitor, i. It has been demonstrated before that mutation of phenylalanine FL in helix 9 of MraY caused resistance against lysis protein E [72,73].

An interaction between F and glutamic acid E with the peptide motif arginine-tryptophan-x-x-tryptophan RWxxW, x represents an arbitrary amino acid was found.

structure activity relationship of penicillin and alcohol

Mutants FL and EA showed reduced or no detectable enzyme inhibition, thus indicating a secondary binding site for potential MraY inhibitors. Nevertheless, it remains unclear how binding at helix 9 can inhibit MraY function and further studies are probably inevitable [74]. In order to investigate the biological potencies of MraY inhibitors such as the muraymycins, in vitro assay systems are needed.

A widely used and universal method to evaluate the in vitro activity of potential agents against certain bacteria is the determination of minimum inhibitory concentrations MIC. SUMMARY OF THE INVENTION Briefly, according to the process or method of this invention phosgene is commingled with a liquid mixture of the selected penicillin or pencillin sulfoxide acid, the selected alcohol, and a tertiary amine or equivalent hydrogen halide absorber in an inert organic diluent at temperatures low enough to control the exothermic reaction which takes place and thus to avoid any substantial degradation of penicillin ester products, or reactants.

The penicillin acid or penicillin sulfoxide and alcohol and base should not be added to the phosgene in undiluted form, however.

structure activity relationship of penicillin and alcohol

Conducting the process in this invention may involve an in situ formation of the carbonic acid anhydride or the pencillin acid chloride, but contrary to the disadvantages of some of the prior art methods, each of these two possible intermediates is desirable for penicillin ester formation, and in addition, as a result of this invention it becomes unnecessary to separately prepare haloformate reactants. Any excess phosgene used in the process is readily neutralized by the excess base present in the mixture, or destroyed by the water which is added after the phosgene addition is completed.

The water or other separating medium which may be used precipitates the penicillin ester product, which crude precipitated product may be readily separated from the reaction mixture in conventional manner. In place of phosgene, carbonyl bromide, thiophosgene, carbonyl fluoride, or other equivalent reagents may be used, but for economical reasons phosgene is preferred. The esterification reaction is conducted in the presence of a hydrogen halide absorber or acid acceptor substance which is preferably an inexpensive tertiary amine which is soluble in the organic liquid diluent, but inexpensive alkali metal bicarbonates such as the lithium, sodium, and potassium bicarbonates could be used.

US3586667A - Penicillin esterification process - Google Patents

Examples of inexpensive hydrogen halide absorbers include the trialkylamines, such as the C to C trialkylamines, e. Organic liquid diluents which may be used include the common aromatic solvents such as benzene, toluene, and the xylenes, the halogenated lower aliphatic hydrocarbons such as methylene chloride, chloroform, carbon tetrachloride, lower alkanones such as acetone, methyl ethyl ketone, and the like, lower acyl nitriles such as acetonitrile, propionitrile, and the like, as well as lower dialkylsulfoxides such as dimethylsulfoxide, diethylsulfoxide, the lower dialkylacylamides such as dimethylformamide, diethylformamide, ethers such as dioxane, tetrahydrofuran, diethyl ether of diethylene glycol, lower nitro-hydrocarbons such as nitromethane, nitropropane, and the like, and alkyl acylates having up to about 7 carbon atoms, e.

The organic liquid diluent is inert in that it does not interfere significantly with the esterification reaction. The diluent is also preferably water miscible so that the reaction mixture mixes nicely with the water which is added after phosgene addition is completed. A substantially anhydrous liquid medium is preferred for economic reasons but a small amount of water in the system can be tolerated without serious interference. However, it is desirable to keep the Water content in the reaction system below about 5 percent, preferably below about 2.

Excess alcohol could be used as the organic liquid diluent but is not preferred since the excess alcohol competes for the added phosgene to form side-reaction products, thus involving waste of reactants. The common inert organic liquid diluent for the process of this invention will be selected by those skilled in the art primarily on the basis olflcost and availability.

Numerous such diluents are availa e.

USA - Penicillin esterification process - Google Patents

The penicillin and penicillin sulfoxide acid starting materials are those which have one of the following general formulas: The alkali metal salts of these penicillins such as the sodium and potassium salts can also be used. For reasons of availability and cost phenoxymethyl penicillin, as such, or in its sulfoxide form are preferred. However, it is to be understood that there are literally thousands of penicillins in the prior art to which the process of this invention is applicable in making penicillin and penicillin sulfoxide esters for conversion to corresponding desacetoxycephalosporanate esters in the overall process of converting penicillins to specific cephalosporin antibiotics.

If desired, this process can also be applied to the penicillin nucleus 6-APAif the 6-amino group is suitably protected by known methods. Numerous penicillins derived by fermentation methods known in the prior art e. For practical considerations, the preferred penicillin and penicillin sulfoxide acids for use in the process of this invention are those of the formulas: Penicillins with these representative R groups are examples of the most economically prepared or more readily obtainable by fermentation methods.

The penicillin esters prepared by the method of this invention are useful as intermediates to desacetoxycephalosporin antibiotics in that they can be oxidized by known methods, e.

The ester products of the invention and desacetoxycephalosporins obtained therefrom are conveniently named by useing the penam and cepham nomenclature system. The penam nomenclature system for the penicillins is described by Sheehan, Henery-Logan, and Johnson in the J. In accordance with these systems of nomenclature penam and cepham refer respectively to the following saturated ring system: Thus, for example, penicillin V phenoxymethyl penicillin can be named 6- phenoxyacetamido -2,2-dirnethylpenamcarboxylic acid.

Similarly, a 2,2,2-trichloroethyl penicillin V sulfoxide ester obtained therefrom with 2,2,2-trichloroethanol can be named 2,2,2-trichloroethyl 6- phenoxyacetamido -2,2- dimethylpenamcarboxylate. Other examples of penicillin and penicillin sulfoxide ester products which can be prepared by the process of this invention include: The selected alcohol for penicillin or penicillin sulfoxide ester formation may be any alcohol which forms a readily cleavable penicillin ester group after the heat conversion step or one which forms an orally antibiotically active desacetoxycephalosporanate ester.

Preferred easily cleaved esters are, for example, those obtained from 2,2,2-trichloroethanol, benzyl alcohol, benzyloxymethanol, the methoxy-substituted benzyl alcohols such as 4-methoxybenzyl alcohol, 3-methoxybenzyl alcohol, 3, S-dimethoxybenzyl alcohol, benzhydrol alcohol, bis 4- methoxyphenyl methanol, and the hydroxmic alcohols such as N-hydroxysuccinimide, N-hydroxyphthalimide, as well as phthalimidomethyl alcohol and succinimidomethyl alcohol.

structure activity relationship of penicillin and alcohol

Some cephalosporin antibiotics in the acetoxymethyl ester form are orally absorbed, such as the acetoxymethyl 7- 2'-thienylacetamido cephalosporinate.

When such an antibiotic is being prepared from penicillin or penicillin sulfoxide ester materials, it will be desirable to use acetoxymethanol as the alcohol. Lower alkanols having from 1 to 6 carbon can also be used, but, in general, they form more difiicultly cleavable esters, and therefore are not preferred. The addition of phosgene or similar materials to the mixture of the selected penicillin or penicillin sulfoxide acid, or salt, alcohol, hydrogen halide absorber, and organic liquid solvent or diluent causes an exothermic reaction and evolution of carbon dioxide to occur.

This exothermic reaction can be controlled to a desirable rate by a variety of known methods. The mixture is generally cooled and stirred or otherwise agitated to distribute the heat of reaction.

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Also, the rate of addition of phosgene can be controlled to a slow rate to reduce the requirement for extensive cooling equipment. However, it is generally preferred to cool the mixture to which the phosgene is added to from C. The low temperatures are generally maintained until all of the phosgene has been added, and the exothermic reaction has subsided. When the reaction is completed, as indicated by absence of exothermic heat, or cessation of evolution of CO the penicillin or penicillin sulfoxide ester product can be removed from the reaction mixture by adding water in an amount to precipitate the ester product, and to destroy any excess phosgene in the mixture.

The crude ester if it is an oil can be removed by extraction with an appropriate organic solvent, filtration and purified, e. The penicillin or penicillin sulfoxide acid or salt is preferably mixed with a slight molar excess of the selected alcohol in the organic solvent to insure complete reaction of the more expensive penicillin material. An excess of hydrogen halide absorber, such as a tertiary amine, is preferably used to insure complete reaction of the phosgene and its by-products.

Care is taken in the equipment used to provide for the release of evolved gases such as carbon dioxide from the reaction mixture. The invention is further illustrated by the following detailed examples which show the preparation of a penicillin sulfoxide before esterification, and the esterification procedure. The penicillin V slowly dissolved giving a clear, pale light yellow solution. After about 2 hours at 15 to 20 C. Stirring was continued for a total reaction time of 4 hours.

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The mixture was cooled to about 0 C. The precipitate was filtered, washed with 5 liters of water, and dried for 18 hours at 60 C. There was thus obtained g. The infrared IR and nuclear magnetic resonance NMR spectra and melting point data were identical with the data of a sample of known penicillin V sulfoxide. Penicillin V sulfoxide, 2,2,2-trichloroethyl ester A stirred mixture of g.

structure activity relationship of penicillin and alcohol

Carbon dioxide evolution was extremely rapid throughout the phosgene addition. Stirring was continued for an additional 30 minutes at 5 to 10 C. Then 2 liters of water was added dropwise in 60 minutes at 0 to 10 C.