Antibacterial enzyme inhibitors

H. Umezawa published some 1200 papters covering many new antibiotics ( 100 for antibacterial, —70 for antitumor, and > 50 for enzyme inhibitors). Here are listed only the most representative reports. 

The methylation of deoxyuridine monophosphate (dUMP) to thymidine monophosphate (TMP), catalyzed by thymidylate synthase, is essential for the synthesis of DNA. The one-carbon fragment of methy-lene-tetrahydrofolate is reduced to a methyl group with release of dihydrofolate, which is then reduced back to tetrahydrofolate by dihydrofolate reductase. Thymidylate synthase and dihydrofolate reductase are especially active in tissues with a high rate of cell division. Methotrexate, an analog of 10-methyl-tetrahydrofolate, inhibits dihydrofolate reductase and has been exploited as an anticancer drug. The dihydrofolate reductases of some bacteria and parasites differ from the human enzyme inhibitors of these enzymes can be used as antibacterial drugs, eg, trimethoprim, and anti-malarial drugs, eg, pyrimethamine. 

Zwitterionic character is notable in several therapeutic area series, e.g. in angiotensin-converhng enzyme inhibitors, quinolone anhbacterials and thrombin inhibitors. The aqueous solubiUty measurement of zwitterions is very pH dependent as might be expected. The relationship of aqueous solubiUty to ionization state is extraordinarily complex if the zwitterion is of the type capable of an equi-Ubrium between true zwitterion and formally neutral forms (e.g. as in a quinolone antibacterial). For these types of complex equilibria, salt effects on solubility may be unexpectedly large, e.g. solubility unexpectedly may track with the chaotropic character of the salt... 

Now we come to the question what is the basis of the antibacterial action of the sulfa drugs Many useful drugs in human medicine are enzyme inhibitors, small molecules that frequently bear a structural resemblance to the substrates or products of enzyme-catalyzed reactions. So it is with the sulfonamides. 

Competitive inhibitors bind to specific groups in the enzyme active site to form an enzyme-inhibitor complex. The inhibitor and substrate compete for the same site, so that the substrate is prevented from binding. This is usually because the substrate and inhibitor share considerable stmctural similarity. Catalysis is diminished because a lower proportion of molecules have a bound substrate. Inhibition can be relieved by increasing the concentration of substrate. Some simple examples are shown below. Thus, sulfanilamide is an inhibitor of the enzyme that incorporates j9-aminobenzoic acid into folic acid, and has antibacterial properties by restricting folic acid biosynthesis in the bacterium (see Box 11.13). Some phenylethylamine derivatives, e.g. phenelzine, provide useful antidepressant drags by inhibiting the enzyme monoamine oxidase. The cA-isomer maleic acid is a powerful inhibitor of the enzyme that utilizes the trans-isomer fumaric acid in the Krebs cycle. 

A considerable number of enzymes occupy a central and crucial role in the activity of drugs. Dihydrofolate reductase, an enzyme involved in purine and amino acid biosynthesis, is the target of antibacterial sulfanilamides, which act both as bacteriostatics and antimalarials. These drugs act on the enzyme in different ways, some being so-called antimetabolites (i.e., reversible enzyme inhibitors). Some diuretics act on carbonic... 

A wide variety of a-tnfluoromethyl ab-ammo acids ate readily available from the reaction of 5-fluoro-4-tnfluoromethyl-l,3 azoles with allyhc alcohols [755, 759] a-Tnfluoromethyl-substituted a-amino acids show antibacterial and antihy pertensive activity Some are highly specific enzyme inhibitors (suicide inhibitors) and may be important as bioregulators [740] Furthermore, they are interesting candidates for peptide modification... 

Peptides with C-terminal phosphonates, initially reported to have antibacterial properties, have also been found to possess inhibitory properties toward serine proteases)28 The synthesis of peptide phosphonates (Section 15.1.8) usually requires protection of the phos-phonic moiety as a diester, followed by selective deprotection in the final stage. The importance of peptide thiols (Section 15.1.9) is exemplified by captopril, an orally active angiotensin converting enzyme inhibitor used as a treatment for hypertension)29 These peptide thiols are prepared by the reaction of sulfanylalkanoyl amino acids with a-amino esters followed by deprotection of carboxy and sulfanyl groups. Other peptide thiols have been reported to be inhibitors of zinc metalloproteases, collagenases, and aminopeptidases. 

With the exception of S-metolachlor, all the molecules listed under the column Final Target are used in pharmaceutical formulations. Dilitiazem is a Ca2+ antagonist, while Cilazapril is an angiotensin-converting enzyme inhibitor. Levofloxacin is an antibacterial, and cilastatin is used as an in vivo stabilizer of the antibiotic imipenem. S-metolachlor is a herbicide sold under the trade name of DUAL MAGNUM. Although the structures of the final targets are more complex than those of the intermediates, enantioselective syntheses of the intermediates are the most crucial steps in the complex synthetic schemes of these molecules. 

The bacteriostatic activity of a series of substituted trans-3-benzoylacrylic acids has been successfully correlated by Hansch linear free energy relations involving polar and partition substituent constants. The activity-lipophilicity relations for this series closely parallel those found previously for other antibacterial agents, with an ideal lipophilic character for gram-positive cells of 6.1 and, for linear dependence, a slope of 0.7. A polar reaction constant, p, of about —0.6 to —0.7 is given. A possible mode of action for these acids and their related substituted cis- and trans-3-benzoyl acrylic acids and esters is discussed as an enzyme-inhibitor interaction. 

Enzyme inhibitors such as cloxacillin and methicillin have been shown to potentiate the action of certain penicillins and cephalosporins against Ps. aeruginosa Figure 7.7). Thus, the presence of cloxacillin, which is a strong inhibitor of the inducible enzyme, potentiates the effect of cephaloridine which alone is susceptible to hydrolysis by the pseudomonas lactamase. Cloxacillin shows no antibacterial activity against... 

Keratomycosis is present. This should be considered in all cases where combined antibacterial and enzyme inhibitor therapy has failed to halt the progression of the ulcer within 2 to 3 days or sooner where the clinical presentation suggests fungal involvement. 

Difflam benzydamine. diflorasone flumethasone. diflorasone diacetate flumethasone. difloxacin [inn] (difloxacin hydrochloride [usan]) is a quinolinecarboxylic acid ANTIBACTERIAL (a DNA gyrase enzyme inhibitor). 

SUltamieillin [ban, inn, usan] is a semisynthetic (penicillin) ANTIBIOTIC, a prodrug of ampicillin and sulbactam, joined by a double ester, where the latter is an enzyme inhibitor that is resistant to P-lactamase and inhibits this penicillindegrading enzyme. It can be used clinically as an ANTIBACTERIAL to treat certain infections. 

RECEPTOR ANTAGONIST reported to have little sedative action, tazifylline hydrochloride tazifyUine. tazobactam (inn] (tazobactam sodium [usan]) is an ENZYME INHIBITOR active against the P-lactamase ( penicillinase ) enzymes produced by Gram-positive and -negative bacteria. Clinically, it can be used co-administered with -lactamase susceptible penicillins and cephalosporins, enhancing their antibacterial actions, tazobactam sodium tazobactam. 

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