Theoretical calculations of β-lactam antibiotics

Summary We carried out a comprehensive theoretical study on the alkaline hydrolysis of the bicyclic system of penicillins (a four-member ring fused to a thiazolidine ring) on the basis of aB _AC2 mechanism. We assayed the MINDO/3, MNDO, and AM1 semi-empirical calculation methods in order to determine their suitability for studying -lactam rings.Both the geometric and the energetic results obtained for the different intermediate states were compared with literature values — chiefly those determined byab initio methods — with which they proved to be very consistent.The conformation of the carboxyl group at position 3 was found to be rather significant to the determination of the energy of the different reaction maxima and minima.     

Prediction of the activity of β-lactam antibiotics

The pharmacological properties of penam, 3-cepheme, and semisynthetic penicillins were predicted by means of the ORAKUL automated system. A comparative evaluation of the similarity between the structures of these compounds and the structures of 8800 biologically active substances in the data base of the system made it possible to uncover the high probability of the manifestation of anti-inflammatory, analgesic, antitumorigenic, antiallergic, and anticoagulant activity by structural analogs of -lactam antibiotics.Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 4, pp. 555–564, April, 1992.     

Molecular evolution of bacterial β-lactam resistance

Background: Two groups of penicillin-destroying enzymes, the class A and class C β-lactamases, may have evolved from bacterial transpeptidases that transfer x-d-Ala-d-Ala peptides to the growing peptidoglycan during cell wall synthesis. Both the transpeptidases and the β-lactamases are acylated by β-lactam antibiotics such as penicillin, which mimic the peptide, but breakdown and removal of the antibiotic is much faster in the β-lactamases, which lack the ability to process d-Ala-d-Ala peptides. Stereochemical factors driving this evolution in specificity are examined.Results: We have compared the crystal structures of two classes of β-lactamases and a β-lactam-sensitive d-alanyl-d-alanine-carboxypeptidase/transpeptidase (DD-peptidase). The class C β-lactamase is more similar to the DD-peptidase than to another β-lactamase of class A.Conclusions: The two classes of β-lactamases appear to have developed from an ancestral protein along separate evolutionary paths. Structural differentiation of the β-lactamases from the DD-peptidases appears to follow differences in substrate shapes. The structure of the class A β-lactamase has been further optimized to exclude d-alanyl peptides and process penicillin substrates with near catalytic perfection. Keywords: drug resistance, enzymology, penicillin antibiotics, protein ancestry Received: 7 October 1996     

γ-Lactam analogues of monocyclic β-lactam antibiotics

γ-Lactam analogues of monocyclic β-lactam antibiotics, the oxamazins, have been prepared from N-protected γ-nitro-α-amino acid esters. Unlike the oxamazins, these higher homologues are devoid of biological activity.     

Synthesis and biological investigation of the β-thiolactone and β-lactam analogs of tetrahydrolipstatin

The synthesis of β-thiolactone and β-lactam analogs of tetrahydrolipstatin is described from a common late-stage β-lactone derivative. These analogs, and a cis-disubstituted β-lactone analog of tetrahydrolipstatin, were screened for activity against porcine pancreatic lipase and for inhibition of cell growth of a panel of four human cancer lines.     

The stereoselective synthesis of γ-lactam derivatives through N(1)-C(4) one carbon ring expansion of β-lactam derivatives

The base induced ring opening of β-lactam derivatives, 3, 5, 7, 9, 11 with LDA gave γ-lactam derivatives, 4, 6, 8, 10, 12 stereoselectively. The γ-lactam derivatives were formed stereoselectively depending on C-3 substituent of β-lactam derivatives.     

Design, synthesis and evaluation of β-lactam antigenic peptide hybrids; unusual opening of the β-lactam ring in acidic media

β-Lactam peptides were envisioned as conformational constraints in antigenic peptides (APs). Three different β-lactam tripeptides of varying flexibility were prepared in solution and incorporated in place of the central part of the altered melanoma associated antigenic peptide Leu(27)-Melan-A(26-35) using solid phase synthesis techniques. Upon TFA cleavage from the solid support, an unexpected opening of the β-lactam ring occurred with conservation of the amide bond. After adaptation of the solid phase synthesis strategy, β-lactam peptides were successfully obtained and both opened and closed forms were evaluated for their capacity to bind to the antigen-presenting class-I MHC HLA-A2 protein system. None of the closed β-lactam peptides bound to HLA-A2, but their opened variants were shown to be moderate to good HLA-A2 ligands, one of them being even capable of stimulating a Melan-A-specific T cell line.     

Highly diastereoselective indium-mediated synthesis of β-lactam carbohydrates from imines

A simple and very effective approach to versatile carbohydrate β-lactam synthons of predictable absolute configuration has been developed. The procedure, which is based on the indium-mediated reaction of imines and bromoesters, was applied to the enantioselective synthesis of 3-monosubstituted and 3-disubstituted β-lactams from readily available carbohydrates. The opening of the β-lactamic ring gave rise to the corresponding sugar-derived β-amino acids. Transformation of the β-lactams into the corresponding azetidines was also achieved.     

The Preparation of β-Hydroxysulfoxides

. Oxidation of β-hydroxy thioethers with MnO₂-aqu. 35%/HCl in methanol gives β-hydroxy sulfoxides in high yields.     

Synthesis of 4-aryl-substituted β-lactam enantiomers by enzyme-catalyzed kinetic resolution

Enantiopure 4-phenyl- and 4-(p-tolyl)-2-azetidinones 3a, 3b, 4a and 4b (with e.e.s of ≥96%) were prepared through lipase-catalyzed asymmetric butyrylation of the primary OH group of N-hydroxymethylated β-lactams (±)-5 and (±)-6 at the (R)-stereogenic centre or by lipase-catalyzed asymmetric debutyrylation of O-butyryloxymethyl-2-azetidinones (±)-7 and (±)-8 at the (R)-stereogenic centre. The ring-opening of lactams 5a, 5b, 6b and 8a with HCl/EtOH afforded the corresponding β-amino ester enantiomers 9a, 9b, 10a and 10b with e.e.s of ≥92%.     

Semipinacol rearrangement of cis-fused β-lactam diols into keto-bridged bicyclic lactams

The 6-azabicyclo[3.2.1]octane ring system, prevalent in a range of biologically active molecules, is prepared through a novel semipinacol rearrangement utilizing a cyclic phosphorane or sulfite intermediate. The rearrangement proceeds with exclusive N-acyl group migration of a β-lactam ring and results in carbonyl functionality at the 7- and bridging 8-position of the bicycle. Precursor ring-fused β-lactam diols are prepared through a sequence of 4-exo trig carbamoyl radical cyclization, regioselective dithiocarbamate group elimination, and dihydroxylation.     

l-Proline organocatalyzed Michael synthesis of monobactam and carbapenem β-lactam cores

Herein, we report the development of mild, organocatalyzed routes to novel β-lactam carbapenem derivatives through Michael type CC bond forming reactions. The same methodology, followed by a retro-Dieckmann reaction, provides a pathway to novel and highly functionalized monobactam derivatives, another class of valuable β-lactam antibiotics.     

A C-N insertion of β-lactam to benzyne: unusual formation of acridone

Intermolecular insertion of benzyne into the C-N bond of a β-lactam is described. This σ-insertion is followed by ring expansion that produces dihydroquinolinone, which rapidly reacts with an additional benzyne unit to afford an acridone through intramolecular C-C bond formation to the carbonyl group and rapid elimination of ethylene.     

Advances in the chemistry of β-lactam and its medicinal applications

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Micellar catalysis in reactions of some β-lactam antibiotics with p -dimethylaminobenzaldehyde

Kinetic study of the reactions of amoxicillin (I), ampicillin (II) and cephlaxin (III) with p-dimethylaminobenzaldehyde (DAB) in weakly acidic EtOH/H₂O solution has been investigated using spectrophotometric method. Relatively slow reversible reactions of first order with respect to the antibiotic have been found. A derived equation for detecting the existence of reversibility from the linearity has been introduced. The effect of anionic surfactants (sodium dodecyl sulfate, SDS) on the kinetic of these reactions in aqueous solution has been studied. The presence of 0.005 M of SDS increases the rate constants by 4.3, 2 and 3.3 times for I, II and III, respectively. The consequence of the rate constants have a similar order in absence and presence of SDS; III > II > I. The rate constants pass through maxima with increasing SDS concentration followed by a gradual but steady decrease in the rate as the surfactant concentration increases further. Multiple linear regression method has been performed to evaluate the binding constants of each drug and DAB with SDS from the resulted kinetic data. The results suggest using multiple linear correlation method for such calculations, which is more accurate, reliable and less time consuming. The calculated binding constants between these drugs with SDS are following the consequence I > II > III which is related to the differences in their substitutions. The kinetic results were employed for spectrophotometric microdetermination of these drugs (I–III) in aqueous solution. The method was based on the reaction of β-lactam with an excess of DAB in presence of SDS and HCl (pH 2) at a wavelength 410 nm. The results indicate that the presented method is simple, precise and accurate. This method is applied to bulk antibiotics and some of their pharmaceutical preparations.     

Asymmetric synthesis of aminocyclooctenecarbonitriles: Cyclooctene β-lactam and hydroxyaminocyclooctene carboxylic precursors

Enantiopure β-aminocyclooctenenitriles, as precursors of β-amino acids and β-lactams, were synthesized from a readily available chloroalkene nitrile and (S)-methylbenzylamine via a straightforward substitution reaction and purified by crystallization. Acidic hydrolysis of the nitrile groups to their corresponding amides followed by DCC assisted carbonyl group activation gave novel α,β-unsaturated lactams. The treatment of 3-bromo-8-chlorocyclooctenecarbonitrile with (S)-methylbenzylamine furnished a diastereomeric mixture of bromoaminocyclooctenecarbonitriles via an S_N2′ pathway rather than bromide substitution via an S_N2 pathway. The diastereomeric mixture of bromoaminocyclooctanecarbonitriles provided two novel aziridines upon heating. TFA catalyzed aziridine ring opening gave γ-hydroxyl-β-aminocyclooctenecarbonitriles and γ-amino-β-hydroxycyclooctenecarbonitriles.     

Antagonism of chemical genetic interaction networks resensitize MRSA to β-lactam antibiotics

Antibiotic drug resistance among hospital and community acquired methicillin resistant Staphylococcus aureus (MRSA) has dramatically eroded the efficacy of current therapeutics. We describe a chemical genetic strategy using antisense interference to broadly identify new drug targets that potentiate the effects of existing antibiotics against both etiological classes of MRSA infection. Further, we describe the resulting chemical genetic interaction networks and highlight the prominent and overlapping target sets that restore MRSA susceptibility to penicillin, cephalosporins, and carbapenems. Pharmacological validation of this approach is the potent synergy between a known inhibitor to a member of this genetic potentiation network (GlmS) and a broad set of β-lactam antibiotics against methicillin resistant Staphylococci. Developing drug-like leads to these targets may serve as rational and effective combination agents when paired with existing β-lactam antibiotics to restore their efficacy against MRSA.     

The reaction of β-lactam carbenes with 3,6-dipyridyltetrazines: switch of reaction pathways by 2-pyridyl and 4-pyridyl substituents of tetrazines

The reactions of β-lactam carbenes with both 3,6-di(2-pyridyl)tetrazine and 3,6-di(4-pyridyl)tetrazine were studied. It was found that β-lactam carbenes reacted with 3,6-di(2-pyridyl)tetrazine to produce 5-triazolo[1,5-a]pyridylpyrrol-2-ones in good yields, while with 3,6-di(4-pyridyl)tetrazine, they afforded pyrido[c]cyclopenta[b]pyrrol-2-ones in moderate yields. Both reactions were proposed to follow cascade mechanisms containing a 3,6a-dipyridylpyrrolo[3,2-c]pyrazol-5-one intermediate. The different pathways of the transformation of pyrrolo[3,2-c]pyrazol-5-ones were switched by the 2- and 4-pyridyl substituents. This work not only provided a simple and efficient strategy for the construction of novel triazolo[1,5-a]pyridine and pyrido[c]cyclopenta[b]pyrrole derivatives, respectively, but also revealed two different thermal transformation patterns of 3H-pyrazole compounds.