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Nitroveratrole esters (i.e. 4,5-dimethoxy-2-nitrobenzyl (NV) esters) of penicillin and cephalosporin derivatives have been prepared in the course of a program dedicated to photosensitive protein microarrays. Surprisingly, some molecules revealed to be acylating inhibitors of R39 and BlaR-CTD proteins (two representative Penicillin Binding Proteins (PBPs)), while being bad substrates of beta-lactamases (bacterial defense enzymes). Electrostatic potential maps and docking experiments showed that the 2-nitro group of NV esters could play the role of a carboxylate in the penam series.

By conformational analysis using the CNDO method we have attempted to outline the common molecular fragments for different arylacetic acids with anti inflammatory activity. The calculated energies for the different conformations give evidence for a conformation common to all these products.

Thiamine and its three phosphorylated derivatives (mono-, di- and triphosphate) occur naturally in most cells. Recently, we reported the presence of a fourth thiamine derivative, adenosine thiamine triphosphate, produced in Escherichia coli in response to carbon starvation. Here, we show that the chemical synthesis of adenosine thiamine triphosphate leads to another new compound, adenosine thiamine diphosphate, as a side product. The structure of both compounds was confirmed by MS analysis and H-1-, C-13- and P-31-NMR, and some of their chemical properties were determined. Our results show an upfield shifting of the C-2 proton of the thiazolium ring in adenosine thiamine derivatives compared with conventional thiamine phosphate derivatives. This modification of the electronic environment of the C-2 proton might be explained by a through-space interaction with the adenosine moiety, suggesting U-shaped folding of adenosine thiamine derivatives. Such a structure in which the C-2 proton is embedded in a closed conformation can be located using molecular modeling as an energy minimum. In E. coli, adenosine thiamine triphosphate may account for 15% of the total thiamine under energy stress. It is less abundant in eukaryotic organisms, but is consistently found in mammalian tissues and some cell lines. Using HPLC, we show for the first time that adenosine thiamine diphosphate may also occur in small amounts in E. coli and in vertebrate liver. The discovery of two natural thiamine adenine compounds further highlights the complexity and diversity of thiamine biochemistry, which is not restricted to the cofactor role of thiamine diphosphate.

Novel bicyclic 2-azetidinones, in which the P-lactam moiety is embedded in a 1,3-bridging large ring, have been studied experimentally and theoretically. The compounds were prepared from (3S,4R)-3-[(1R)-1-(tert-butyldimethylsilyloxy)-ethyl]-4-propyl-2-azetidinone (3) by sequential N1 and O5 functionalization with omega-alkenyl chains by acylation and/or alkylation reactions. Cyclization by ring-closing metathesis (RCM) gave a series of 12- and 13-membered-ring compounds 7, 12b,c, 17b,c and 24 featuring the internal HC=CH double bond with a preferential (E) configuration, and then the corresponding saturated 1,3-bridged bicycles 8, 13b,c, 18b,c and 25 after hydrogenation. Bridges of 9-11 atoms were inaccessible and bridges of 12 atoms appeared favoured over those with 13 atoms according to ab initio quantum chemistry calculations. This was confirmed experimentally because w-alkenyl double-bond migration occurred in competition with the RCM reaction in the case of 13-atom precursors, leading to a mixture of 12- and 13-membered rings. Modelling of the reactivity of our 1,3-bridged 2-azetidinones, towards hydrolysis and processing by serine enzymes, highlighted the important roles of geometrical and conformational factors and predicted a modest "acylating power" in comparison with classical penam compounds (antibiotics). Biochemical evaluation against the R39 bacterial enzyme (D,D-peptidase) revealed a weak inhibition effect of the 13-membered-ring 1,3-bridged O,N-bis(acylated) azetidinones 7 and 8. ((c) Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2009)

Dans cet article, sont decrites differentes modifications apportees a la version originale du programme CNINDO. II est montre que l'usage d'un procede d'extrapolation accelere sensiblement la convergence du processus SCF.

A series of six radical cations of the type (DLD)+ was investigated at the ab initio unrestricted Hartree–Fock level. One localized and one delocalized conformation were systematically searched by full geometry optimization. At both nuclear arrangements, mostly found as being minima in the symmetry-restrained Hartree–Fock framework, excitation energies were calculated through the expansion of the wave function on single electronic excitations of the Hartree–Fock fundamental determinant and at the unrestricted Hartree–Fock or at the multiconfigurational self consistent field levels. Few calculations were also performed by taking into account some part of the electronic correlation. Except for N,N,N′,N′-tetramethyl p-phenylenediamine, all the studied compounds are localized stable cations, at the symmetry-restrained Hartree–Fock level. However, the reoptimization of their wave function changes this observation since only three of them seem to conserve a localized stable conformation. Most of the studied systems are characterized by one or two excited electronic states very close to the fundamental one and should thus present an unresolved broadened first absorption band in the near-infrared region. These features are in agreement with the available experimental data. Strong Hartree–Fock instabilities are found for the delocalized structure and put in relation with the existence of the large nonadiabatic coupling in this conformational region. The solvent influence is discussed in the Onsager dipolar reaction field framework. © 2000 John Wiley & Sons, Inc. Int J Quant Chem 76: 552–573, 2000

The acylation reaction of β-lactamases by β-lactam compounds is modeled as a one-step process. Twenty seven transition-state models are investigated at the restricted Hartree–Fock (RHF) level within the minimal MINI-1′ basis set. These transition states differ by the nature of both the substrate and the amino acids constituting the reactive nucleophile. The intrinsic reactivity of the class-A and class-C β-lactamases are under concern. Eight transition-state models were docked in a class-A β-lactamase, TEM1, as optimized with the benzylpenicillin at the molecular mechanics level. In the proposed one-step acylation process, only two amino acids are directly involved, the usual nucleophilic serine, S70 in TEM1, and a close serine or tyrosine, S130 in TEM1, Y150 in P99. The lysine close to these two residues, K73 in TEM1, plays only an indirect role in the process. ©1999 John Wiley & Sons, Inc. Int J Quant Chem 73: 161–174, 1999

This work proposes a very detailed ab initio study of the hypothesis for a one-step serine protease acylation process with one water molecule acting as the main catalyst reactant. For the 11 increasing complexity models considered, the minimum and transition state conformations for the reaction are determined by full geometry optimizations at the ab initio self-consistent field (scF) levels within several basis sets, from MINI-1 to 6-31G, and, for the smallest complexes, at the post-SCF MP2 level within the 6-31G** basis set. The related thermodynamical quantities are calculated for all the conformations. The influence of the oxyanion hole stabilizer and of the dyad His57-Asp102 is quantified and a very good agreement is obtained with point mutagenesis. The activation barrier is found in the range 15-18 kcal/mol. (C) 1996 John Wiley & Sons, Inc.

The electrostatic potential (EP) and the polarization correction (PL) on the EP were calculated for four aromatic compounds: benzene, chlorobenzene, phenol, and benzoic amide, at the ab initio SCF level within two basis sets: 6-31G ** and MINI-1. One calculation was performed using the polarized MINI-1 ** basis set. The quantity total interaction energy (TEH) defined as -EP+PL can be used as an indicator of the nucleophilic attack preferential position. By reference to 6-31G ** , MINi-1 provides very satisfactory results. Moreover, the MINI-1 ** results are very similar to the MINI-1 ones

This work analyses the adequacy of an analytical electrostatic energy formulation within the CNDO framework to predict the stable conformations of large molecular complexes. Comparisons are made with abinitio results for small systems such as water-formamide, methanol-water-imidazole, or guanine-cytosine and with AM1 results for two large systems: a molecular tweezer + the 9-methyladenine complex and a model active site of the α-chymotrypsin and its ligand complex. This approach is efficient in providing reliable confromers for large molecular systems in a very fast way. © 1993 John Wiley & Sons, Inc.

Acylnitroso dienophile 3 derived from D-bornane-10,2-sultam undergoes cycloaddition with high yields and complete facial selectivity to cyclopentadiene and cyclohexadiene. When the nitroso group is attached to the sultam nitrogen, it is no longer reactive in Diels-Alder reactions.

The series of new bis(tetrathiafulva1ene) [bis(TTF)] compounds 10-12a,b have been synthetized with the TTF-like synthon 8a,b, previously used to prepare the pyrazine-fused bis("F) 7a,b. These compounds exhibit four reversible sequential one-electron oxidation steps, on the basis of cyclic voltammetry. For the cation radicals 7b.+,10 .+,and 12.+, generated electrochemically, rather intense and broad bands in the near-IR region, specific of class 11 mixed valence compounds, were found. Theoretical calculations at the semiempirical AM1 level as well as at the ab-initio level indicated that these cation radicals are charge-distributions localized as related to mixed valence species. These calculations also allowed the low-energy absorption bands to be assigned to intervalence transitions; these transitions imply the existence of multiple low-lying excited states that are non-adiabatically coupled to the ground-state of these open-shell species.

A series of new enantiomerically pure acylnitroso compounds have been prepared and tested as dienophiles for the asymmetric oxyamination of dienes. Very high selectivities were obtained with acylnitroso compounds derived from diphenylmethoxymethyl pyrrolidine 2c, the C-2-symmetric pyrrolidines 2d-e and camphorsultam 2f. (C) 1998 Elsevier Science Ltd. All rights reserved.

A series of imidazolopyrazinones 3, substituted at C-2, and C-2/C-6, has been prepared. The compounds behaved as quenchers of superoxide anion. The more active compounds are structurally related to coelenterazine, a natural substrate of marine bioluminescence. Theoretical parameters based on Hartree-Fock instabilities have been examined.

The relationship between angular strain and (re)activity of bicyclic 2-azetidinones is still an open question of major concern in the field of penicillin antibiotics. Our study deals with original 13-membered-ring 1,3-bridged 2-azetidinones related to the carbapenem family, and featuring a "planar amide" instead of the "twisted amide" typical of penam derivatives. The bicycles 11 and 12 were obtained from acetoxy-azetidinone 7, via the key-intermediate 10, by using the RCM (ring closing metathesis) strategy. Theoretical predictions and experimental results of hydrolysis showed that the large bicycle 12, endowed with high conformational flexibility, is more reactive than the bicycle 11, including a C=C bond of E configuration, and the monocyclic 2-azetidinone precursor 10. The processing of 2-azetidinones 10-12 in the active site of serine enzymes has been computed by ab initio methods, considering three models. Due to geometrical parameters of the enzymic cavity (nucleophilic attack from the alpha-face), precursor 10 was predicted more active than 11 and 12 in the acylation step by Ser-OH. Indeed, bicycles 11 and 12 are modest inhibitors of PBP2a, while 10 is a good to excellent inhibitor of PBP2a and R39 bacterial enzymes. (C) 2008 Elsevier Masson SAS. All rights reserved.

As a further phanmacomodulation of benzamide derivatives, two structural modifications were introduced by synthesizing pyridinesulfonamides 5 and 6 (Scheme). The pharmacological profile of substituted benzamides such as metoclopramide (2) is not retained in the pyridine-sulfonarm'des 6: the latter have very low toxicity but do not exhibit any affinity for D2 and 5-HT2 receptors, and gastrointestinal prokinetic activity is weak (Table 3), Lipophilicity does not seem to be a determining factor for this lack of activity. A conformational analysis shows that the sulfonamide group in 6 is rather unfavorable for an intramolecular H-bond formation when compared to the carboxamide group of, e.g., 2. Nevertheless, the interaction remains possible and leads to a stable conformation (Fig. 1, Table 5.) Moreover, the sp3 character of the sulfonamide N-atom of 6 modifies the relative spatial orientation of one substituent in relation to each of the others. This feature seems to be more important for the observed very low activity than the H-bond formation itself.

A series of 2-aryl-and arylmethyl-3-dialkylphenylsilyl cycloalkanones have been prepared and resolved. The pure enantiomers were reduced to the corresponding cycloalkane derivatives. These were used for the in situ generation of enantiopure cycloalkylsilyl triflimides by protodesilylation with bis( trifluoromethanesulfonyl) imide. The association of a bulky leaving group with a silicon atom carrying large substituents was again shown to favour the complexation of silicon with carbonyl groups: all these trialkylsilyl triflimides showed a high catalytic activity for Diels -Alder reactions. Enantiomeric excesses up to 59% were observed. This is the highest enantioselectivity ever observed for a Diels-Alder reaction catalysed by a silicon Lewis acid. (c) 2007 Elsevier Ltd. All rights reserved.

A new asymmetric synthesis of 2-substituted chiral chromanes has been achieved. The key step is the intramolecular conjugate addition of a phenolic nucleophile on a alpha,beta-unsaturated ester catalyzed by Cinchona alkaloids. The high ee's obtained with cinchonine and its derivatives have been rationalized by ab initio quantum chemistry calculations of transition state structures. (C) 2004 Elsevier Ltd. All rights reserved.