Synthesis of the stereoisomers of a novel antibacterial agent and interpretation of their relative activities in terms of a theoretical model of the penicillin receptor

Wolfe, Saul; Zhang, Caijun; Johnston, Blair D.; Kim, Chan-Kyung

doi:10.1139/v94-134

Cited by 10 publications

(10 citation statements)

References 12 publications

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“…The hydroxypropyl side chain (26) was, therefore, examined. Figure 15 is a stereoscopic view of the structure obtained by docking 3 to one of the conformations of the 3S,8R isomer of 26 (21). This structure is compatible with the formal design requirement depicted in Fig.…”

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confidence: 57%

“…An understanding of the nature of this fit will require bioassay data for each of the four stereoisomers of 26, and, eventually, kinetic studies of the reactions of these compounds with penicillin-recognizing enzymes. The syntheses and bioassays of the four stereoisomers of 26 are reported in an accompanying paper (21). However, because of its chemical instability, binding studies with 26 are not currently planned, unless systematic modification of the lead structure is unable to improve the stability.…”

Section: Bioassay Of 26s and 26r: 26s Is An Antibacterial Agentmentioning

confidence: 99%

See 1 more Smart Citation

Interactive design and synthesis of a novel antibacterial agent

Wolfe¹,

Jin²,

Yang³

et al. 1994

Can. J. Chem.

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. Can. J. Chem. 72, 105 1 (1994). P-Lactam compounds act on penicillin-recognizing enzymes via acylation of the hydroxyl group of an active site serine. When the resulting acyl enzyme is kinetically stable, as in the case of a penicillin-binding protein (PBP), the biosynthesis of a bacterial cell wall is inhibited, and death of the organism results. The de novo design of an antibacterial agent targeted to a PBP might be possible if the three-dimensional structural requirements of the equilibrium (i.e.,fit) and catalytic (i.e. reactivity) steps of the aforementioned enzymatic process could be determined. For a model of the active site of a PBP from Streptomyces R61, the use of molecular mechanics calculations to treat "fit," and ab initio molecular orbital calculations to treat "reactivity," leads to the idea that the carboxyl group (GI) and the amide N-H (G2) of the antibiotic are hydrogen bonded to a lysine amino group and a valine carbonyl group in the enzyme-substrate complex. These two hydrogen bonds place the serine hydroxyl group on the convex face of the antibiotic, in position for attack on the p-lactam ring by a neutral reaction, catalyzed by water, that involves a direct proton transfer to the p-lactam nitrogen. Molecular orbital calculations of structure-reactivity relations associated with this mechanism suggest that C=N is bioisosteric to the p-lactam N-C(=O), comparable to a p-lactam in its reactivity with an alcohol, and that the product RO(C-N)H is formed essentially irreversibly (-AE > 10 kcaUmo1). Accordingly, structures containing a G1 and a G2 separated by a C=N, and positioned in different ways with respect to this functional group, have been synthesized computationally and examined for their ability to fit to the PBP model. This strategy identified a 2H-5,6-dihydro-l,4-thiazine substituted by hydroxyl and carboxyl groups as a target for chemical synthesis. However, exploratory experiments suggested that the C=N of this compound equilibrates with endocyclic and exocyclic enamine tautomers. This required that the C2 position be substituted, and that the hydroxyl group not be attached to the carbon atom adjacent to the C=N. These conditions are met in a 2,2-dimethyl-3-(2-hydroxypropy1)-1,4-thiazine, which also exhibits the necessary fit to the PBP model. Two epimers of this compound have been synthesized, from D-and L-serine. The compound derived from L-serine is not active. The compound derived from D-serine exhibits antibacterial activity, but is unstable, and binding studies with PBP's have not been performed. It is hoped that these studies can be canied out if modification of the lead structure leads to compounds with improved chemical stability. Toutefois, des essais prkliminaires ont suggCrC que le C=N de ce composC serait en Cquilibre avec les Cnamines endocycliques et exocycliques tautombres. Cette caractkristique nCcessite que la position C2 soit substituCe et que le groupe hydroxyle ne soit pas attach6 au carbone adjacent du C=N. On rencontre ces conditions dans une 2,2-dimCthy1-3-(2...

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supporting

confidence: 57%

Section: Bioassay Of 26s and 26r: 26s Is An Antibacterial Agentmentioning

confidence: 99%

Interactive design and synthesis of a novel antibacterial agent

Wolfe¹,

Jin²,

Yang³

et al. 1994

Can. J. Chem.

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“…In subsequent work (69), sterospecific syntheses of the four stereoisomers of 20 were devised, and the activity of the 3 s series and lack of activity in the 3R series were confirmed. The side-chain epimers were found to have comparable activity.…”

Section: Combining "Fit" With "Reactivity" Semiempirical Calculationsmentioning

confidence: 96%

1992 Lemieux Award Lecture Studies related to the penicillin receptor

Wolfe¹

1994

Can. J. Chem.

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The relative antibacterial activities of penicillins and cephalosporins are discussed in terms of their differing abilities to complex to and react with penicillin-binding proteins. The insights gained from such an analysis are being used to attempt the design of new kinds of structures targeted to the penicillin receptor. Details of such design, and examples of several new classes of compounds suggested by this work, are described. Some of these compounds exhibit interesting antibacterial activity.

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“…[86] The optical rotation of (S)-2-fluorooxirane, (S)-2-methyloxirane have been studied extensively, both theoretically, [10,[17][18][19][20][21]24,26,[29][30][31][32]34,35,38,[40][41][42][43][44][45][46][49][50][51]53,55,56,60,68,69,[71][72][73][74][75][76]87,88] and experimentally [60,64,89] and several of the other compounds were after their synthesis characterized by measuring the optical rotation in some solvent. [90][91][92][93][94][95][96][97]…”

Section: Introductionmentioning

confidence: 99%

“…Furthermore, the (R)‐ and (S)‐2‐methylaziridine are useful intermediates for the synthesis of alcohols, amino acids, and nitrogen‐containing heterocycles [86] . The optical rotation of (S)‐2‐fluorooxirane, (S)‐2‐methyloxirane have been studied extensively, both theoretically, [10,17–21,24,26,29‐32,34,35,38,40–46,49–51,53,55,56,60,68,69,71–76,87,88] and experimentally [60,64,89] and several of the other compounds were after their synthesis characterized by measuring the optical rotation in some solvent [90–106] . But we are not aware of calculations of the optical rotations of the other compounds in the literature.…”

Section: Introductionmentioning

confidence: 99%

A Density Functional Theory Study of Optical Rotation in Some Aziridine and Oxirane Derivatives

et al. 2021

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We present time-dependent density functional theory (TDDFT) calculations of the electronic optical rotation (ORP) for seven oxirane and two aziridine derivatives in the gas phase and in solution and compare the results with the available experimental values. For seven of the studied molecules it is the first time that their optical rotation was studied theoretically and we have therefore investigated the influence of several settings in the TDDFT calculations on the results. This includes the choice of the one-electron basis set, the exchange-correlation functional or the particular polarizable continuum model (PCM). We can confirm that polarized quadruple zeta basis sets augmented with diffuse functions are necessary for converged results and find that the aug-pc-3 basis set is a viable alternative to the frequently employed aug-cc-pVQZ basis set. Based on our study, we cannot recommend the generalized gradient functional KT3 for calculations of the ORP in these compounds, whereas the hybrid functional PBE0 gives results quite similar to the long-range correct CAMÀ B3LYP functional. Finally, we observe large differences in the solvent effects predicted by the integral equation formalism of PCM and the SMD variant of PCM. For the majority of solute/solvent combinations in this study, we find that the SMD model in combination with the PBE0 functional and the aug-pc-3 basis set gives the best agreement with the experimental values.

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Synthesis of the stereoisomers of a novel antibacterial agent and interpretation of their relative activities in terms of a theoretical model of the penicillin receptor

Cited by 10 publications

References 12 publications

Interactive design and synthesis of a novel antibacterial agent

Interactive design and synthesis of a novel antibacterial agent

1992 Lemieux Award Lecture Studies related to the penicillin receptor

A Density Functional Theory Study of Optical Rotation in Some Aziridine and Oxirane Derivatives

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