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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.

Strychnos nux-vomica L. (Loganiaceae) is famous for its monomeric alkaloid content, such as strychnine, a convulsant poison. The stem bark of the tree is traditionally used to treat intermittent fever in South East Asia. In various studies, it appeared that dimeric indolo-monoterpenic alkaloids possess a promising activity on Plasmodium falciparum. Three bisindolomonoterpenic alkaloids together with strychnochrysine, previously identified in the root bark of S. nux-vomica, were isolated from the stem bark. The structures of these compounds were established using NMR spectroscopy and mass spectrometry. Stereochemistry of the compounds was confirmed by molecular modelling. This then allowed the structural determination of strychnoflavine, a coloured bisindole alkaloid previously isolated from the root bark of the tree. Moreover, the conformational inversion in alkaloids possessing an ether bond in the strychnane moiety could be easily predicted by specific δ (13)C NMR values. These longicaudatine-type alkaloids were found to display in vitro antiplasmodial activity against a chloroquine resistant strain and a chloroquine sensitive strain. The most interesting was strychnochrysine showing an IC(50) value at around 10 μM.

Artemisinin extracted from Artemisia annua L. proved to be currently, with its derivatives, the most effective drugs against simple and severe malaria, and is also effective on the chloroquine-resistant forms. The advantageous effect of some cyclodextrins (CDs) on artemisinin solubilization was demonstrated by different authors. The present work aims to confirm the effect of several CDs on artemisinin solubilization and to analyse the complexes formed between these CDs and artemisinin in order to understand their solubilization capacities. In this context, solubility studies, liquid-state NMR spectroscopy ( 1H NMR studies and ROESY experiments) as well as theoretical studies (molecular modeling) have been performed. Randomly methylated-βCD, Crysmeb® and hydroxypropylated-γCD were also found to improve the aqueous solubilization of artemisinin as well as βCD, γCD and hydroxypropylated-βCD whose effects were already demonstrated. The best solubilization ability was found with Crysmeb®. The spectroscopic studies showed a lot of interactions between artemisinin and all the CDs studied, but mainly outside the cavity. Molecular modeling confirmed that artemisinin and CDs formed non-inclusion complexes

Since the discovery of penicillin, bacteria have counteracted the action of antibiotics leading to a worrisome situation about antibiotic efficiency. During our research on non-traditional 1,3-bridged β-lactams embedded into macrocycles as potential inhibitors of Penicillin Binding Proteins (PBPs), we unexpectedly synthesized bis-2-oxoazetidinyl macrocycles arising from a dimerization reaction under ring closing metathesis (RCM) conditions. These molecules were revealed to be good inhibitors of the D,D-peptidase from ActinomaduraR39, which is commonly used as a model of PBPs. To pursue the research on this type of novel compounds, a complete family of cyclodimers 4 and 5 was synthesized and evaluated against R39, and high molecular weight D,D-peptidases: PBP2a of methicillin-resistant Staphylococcus aureus and PBP5 of resistant Enterococcus faecium. Some bis-2-oxoazetidinyl macrocycles exhibited very promising activities against PBP2a. In order to explain the biological results, docking experiments of one cyclodimer (5e) into the R39 and PBP2a crystallographic structures were performed. The 3D structures of all the dimers were studied by quantum chemistry calculations and the reactivity of one cyclodimer (5e) was evaluated using an elaborate model of the R39 active site. Our results highlighted that the activity of the compounds is most probably related to their conformational adaptability, depending on the size of the macrocycles and the geometrical constraints induced by intramolecular H bonds.

During our research on novel, non-traditional, bicyclic β-lactams as potential inhibitors of Penicillin Binding Proteins (PBPs), we focused on the synthesis of 1,3-bridged 2-azetidinones by RCM reaction from 1,3-bis-ω-alkenoyl-3(S)-amino-2-azetidinone precursors. Submitting the precursors to RCM, we faced an unexpected problem: cyclodimerization was the preferred outcome. This peculiar reactivity, explained by a computational study, led to unprecedented bis-azetidinyl-macrocycles acting as potent inhibitors of R39 D,D-carboxypeptidase, a bacterial model enzyme for PBPs.

The hetero Diets-Alder (HDA) reactions of 1-diethoxyphosphony1-1,3-butadiene with various nitroso dienophiles have been studied at the B3LYP/6-31G** level. Structural, energetic and electronic properties are discussed. These cycloadditions with nitroso dienophiles are characterized by a total proximal regioselectivity and an endo selectivity. The influence of the nitroso substitution on the activation barrier and the regiochemistry of the reaction is presented. The analysis of the chemical rearrangement along the intrinsic reaction pathway (IRC), based on bond order and on natural bond orbital (NBO) calculations, emphasizes the polar nature of these cycloadditions. Despite the early and the cyclic nature of the corresponding transition states, a two-center interaction governs this mechanism: these cycloadditions are Polar Diets-Alder reactions (P-DA). (C) 2010 Elsevier B.V. All rights reserved.

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.

The chemical investigation of the liana Strychnos moandaensis De Wild. led to the isolation of moandaensine, a novel dimeric indole alkaloid. The structure was elucidated by a thorough analysis of the spectroscopic data and by molecular modeling. Moandaensine, or methyl (2S)-2-[(2R,3E,12bS)-3ethylidene-2,4,6,7,12,12b-hexahydro-1H-indolo[2,3-a]quinolizin-2-yl]-3-[(2S,3R)-3-ethyl-2-[(1R)-1(hydroxymethyl)-2-methoxy-2-oxo-ethyl]-1,2,3,4-tetrahydroindolo[2,3-a]quinolizin-5-ium-7-yl]

RGD peptides are used in biomaterials science for surface modifications with a view to elicit selective cellular responses. Our objective is to replace peptides by small peptidomimetics acting similarly. We designed novel molecules targeting alpha(v)beta(3) integrin and featuring spacer-arms (for surface grafting), which do not disturb the biological activity, from (l) N-(3-(trifluoromethyl)benzenesulfonyl) tyrosine used as scaffold. Various Arg-mimics were fixed on the phenol function, and the ortho position was used for the coupling of OEG spacers. All peptidomimetics were active in the nM range in a binding test toward human alpha(v)beta(3) integrin (IC(50) = 0.1 to 1.7 nM) and selective versus platelet integrin alpha(IIb)beta(3). Selected compounds revealed excellent ability to inhibit bone cells adhesion on vitronectin. Modeling and docking studies were performed for comparing the most active RGD peptidomimetic to cilengitide, i.e., cyclo-[RGDfN(Me)V]-. Lastly, the adhesion of endothelial cells on a cultivation support grafted with RGD peptidomimetics was significantly improved.

6-Beta-halogenopenicillanates are powerful, irreversible inhibitors of various beta-lactamases and penicillin-binding proteins. Upon acylation of these enzymes, the inhibitors are thought to undergo a structural rearrangement associated with the departure of the iodide and formation of a dihydrothiazine ring, but, to date, no structural evidence has proven this. 6-Beta-iodopenicillanic acid (BIP) is shown here to be an active antibiotic against various bacterial strains and an effective inhibitor of the class A beta-lactamase of Bacillus subtilis BS3 (BS3) and the D,D-peptidase of Actinomadura R39 (R39). Crystals of BS3 and of R39 were soaked with a solution of BIP and their structures solved at 1.65 and 2.2 A, respectively. The beta-lactam and the thiazolidine rings of BIP are indeed found to be fused into a dihydrothiazine ring that can adopt two stable conformations at these active sites. The rearranged BIP is observed in one conformation in the BS3 active site and in two monomers of the asymmetric unit of R39, and is observed in the other conformation in the other two monomers of the asymmetric unit of R39. The BS3 structure reveals a new mode of carboxylate interaction with a class A beta-lactamase active site that should be of interest in future inhibitor design.

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)

The geometry, frequency and intensity of the vibrational bands of miconazole were derived from the density functional theory (DFT) calculations with the hybrid functional B3LYP and the 6-31G(d) basis set. Starting from the fully AM1 optimized geometries of miconazole/βCD/acids complexes, the miconazole/acid dimers were reoptimized at the B3LYP/6-31G(d) level. Three acids were studied: maleic, fumaric and l -tartaric acids. To begin with the vibrational spectral data obtained from solid phase in mid FT-IR spectrum of miconazole and its dimers are assigned based on the results of the normal modes calculations. All the observed spectra and the calculated ones are found to be in good agreement. In a second step, theoretical results allowed the assignment of FT-IR spectrum for the miconazole/HPγCD inclusion complex produced by supercritical carbon dioxide treatment and confirmed the inclusion of miconazole. The experimental spectra for the miconazole/HPγCD/acids complexes prepared by supercritical carbon dioxide processing were also assigned using theoretical results. The results confirmed the presence of a genuine inclusion complex and also the interaction between miconazole and the acid.

The inclusion of miconazole into cyclodextrin cavity has been demonstrated by different authors. Preliminary studies have shown which fragment of the molecule is involved in the inclusion. In the present study, AM1 approximate molecular orbital calculations have been performed on several cyclodextrins complexes (βCD, HPβCD and HPγCD) with miconazole and acidic compounds (maleic, fumaric and L-tartaric acids) as partners. For all the binary complexes, the inclusion of the dichlorobenzene–CH 2 –O-group leads to the most stable complex. For the ternary complexes, depending on their conformation and/or their structures, the acids can either stabilize or destabilize the complex. All the theoretical results were in good agreement with experimental data of miconazole inclusion yields into cyclodextrins. This work clearly demonstrates that the structure of both cyclodextrin and acid plays a key-role in the formation of inclusion complexes.

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.

The inclusion complexes of tagitinin C with beta-, 2,6-di-O-methyl-beta- and gamma-cyclodextrin (CyD) was investigated in aqueous medium. The stoichiometric ratios and stability constants (K(f)) which describe the extent of formation of the complexes have been determined by UV spectroscopy and direct current tast polarography (DC(tast)), respectively. For each complex, a 1:1 molar ratio was formed in solution and the trend of stability constants was K(f) (2,6-di-O-methyl-beta-CyD)K(f) (gamma-CyD)K(f) (beta-CyD). The effect of molecular encapsulation on the photochemical conversion of tagitinin C was evaluated. No significant protection efficacy was noticed with beta- and gamma-CyD for the complexed drug with the respect to the free one. On the other hand, the photochemical conversion rate was slowed in presence of 2,6-di-O-methyl-beta-CyD. Data from (1)H NMR and ROESY experiments provided a clear evidence of formation of inclusion complexes. The lactone, the ester and the unsaturated ketone parts of tagitinin C inserted into the wide rim of the CyDs torus. These experimental results were confirmed by the molecular modeling using semiempirical Austin Model 1 (AM1) method.

The governing parameters for the long-range intramolecular S-to-N acyl transfer in (S)-acyl isopeptides are shown by computational and statistical methods (principal component analysis and cluster analysis) to be driven by enthalpic and geometric effects over the range n = 5-20. The results emphasize the dependency of ΔG(‡) on the geometrical parameters governing the approach of the reactive termini and the importance of stabilizing intramolecular hydrogen bonds in the transition states (TSs), rather than the effects of TS ring-size. The competition between the intra- (uni-) and inter- (bi)molecular acyl transfers were studied for representative examples.

HIV-1 infection of the brain and PAF neurotoxicity are implicated in AIDS dementia complex. We previously reported that a trisubstituted piperazine derivative is able to diminish both HIV-1 replication in monocyte-derived macrophages and PAF-induced platelet aggregation. We report in this work new compounds obtained by modifying its piperazine substituents. The structure-activity relationship study shows that a better dual activity or even pure antiretroviral compounds can be obtained in this series.

The energies of the fundamental and several excited states of tetrapeptide radical cations were determined at the outer valence Green's function (OVGF) level, at three geometries corresponding to the lowest energy conformations: two for the neutral and one for the cation. The conformations were optimized at the density functional theory level within the B3LYP framework. It was found that, from a purely energetic point of view, a charge initially created on the tyrosine chromophore could migrate without any geometrical change and without further activation once the excited electronic state of the ionized chromophore was formed. This migration could reach the NH(2) terminus for the neutral conformations but should stop at the adjacent peptide link for the cation conformation. These results stress the probable influence of the electronic coupling between the states rather than the existence of a barrier on the charge pathway to explain the difference between the peptides in the charge-transfer process leading to the loss of an iminium [NH(2)=CHR](+) cation. The dissociation energy of the asymptote related to the formation of this NH(2) terminus iminium cation was calculated for few species and it appears that the excess energy available for dissociation is significant when starting from the lowest energy conformations of the neutral or the cation, provided that the charge transfer is effective. It was also found that the amino acids did not conserve their energetic properties and their zero order energy levels turned to a complete new energetic scheme corresponding to the conformation of the peptide.

Dynamics of complex molecular systems in generalized coordinates (q,p) using numerical kinetic energy operators is investigated. The kinematical tools necessary for quantum, classical or semiclassical dynamics with or without constraints mainly come from the covariant and contravariant components of the metric tensor and their derivatives up to the second ones. These quantities are computed numerically but without any other approximation than the numerical precision by the code TNUM. This code generates kinetic energy operators in the internal coordinates of the Z-matrix describing the molecular frame geometry in the ab initio quantum chemistry step or in symmetry adapted coordinates [D. Lauvergnat, A. Nauts, J. Chem. Phys. 116 (2002) 8560]. Various reduced dimensionality models can be used in the upgraded code. The interface with an ab initio code is calibrated on a 22-atom system for which a two-dimensional quantum treatment with a constrained Hamiltonian has been carried out previously. The test application concerns the spreading properties of a wave packet in an unstable flat region around a valley ridge inflexion point between two transition states in the Endo-dimerization of cyclopentadiene. We perform here on-the-fly classical or semiclassical dynamics in full or reduced dimensionality.

The triplet Hartree–Fock (HF) instability is investigated through the examples of substituted ethylenes and the small linear conjugated systems butadiene, hexatriene, octatetraene. A statistical analysis is performed for several conformations of the latters. The second eigenvalue of the instability matrix appears to be able to discriminate the groups of unsaturated compounds. The HF instability is largely influenced by conjugation and mesomeric effects and thus by the geometry. The number of π electrons is also an important factor. The electronic correlation related to the HF instability is not quantified by the energy difference between the post-HF and HF levels.

The ability of cyclodextrins (CDs) to increase the solubility of cyproterone acetate (CPA) was previously shown by phase-solubility and NMR studies [1]. In the present work, the influence of various CDs on the stability of CPA was studied in pH 6 and pH 8 aqueous solutions at 25 °C. Different CDs were tested: hydroxypropyl-β-cyclodextrin (HPβCD), randomly methylated β-cyclodextrin (RAMEB), hydroxypropyl-γ-cyclodextrin (HPγCD) and γ-cyclodextrin (γCD). At pH 6, the presence of these CDs reduces the degradation of CPA. Nevertheless, at pH 8, the γ-CD derivatives are ineffective against the degradation of CPA, whereas the β-CD derivatives (HPβCD and RAMEB) allow decreasing CPA hydrolysis. Molecular modeling was performed to theoretically calculate some of the most energetically favorable conformations for γ-CD and RAMEB complexes with CPA. The position of the ester group in the CD cavity seems to be the most important factor influencing the hydrolysis of CPA. Other factors, such as the size of the cavity, the substitution of the CD hydroxyls and the stability constant also have a strong incidence on CPA stability.

4-(Alkylamino)carbonyl-1-(alkoxy)carbonyl-2-azetidinones (9-11) have been prepared in five steps from 4-(benzyloxy)carbonyl-1-(t-butyldimethyl)silyl-2-azetidinone (1). The beta-lactam reactivity of 9 has been established by 1H NMR experiment. Compound 11 was a good reversible inhibitor of PPE and HLE. Based on theoretical design, series of 2-azetidinones (12-17) and 4-(alkoxy)carbonyl-2-azetidinones (18-21) bearing various carbonyl (ester, thiolester, amide) and thiocarbonyl (thioamide) functionalities at position N1 were similarly prepared. In the absence of C4-substituent, the compounds were inactive against elastases. On the other hand, 4-(benzyloxy)carbonyl-1-(ethylthioxy)carbonyl-2-azetidinone (19) and 4-(benzyloxy)carbonyl-1-(benzylamino)thiocarbonyl-2-azetidinone (21) were both good reversible inhibitors, but acting most probably via different mechanisms (enzymic processing of the exocyclic ester function or beta-lactam ring opening).

We compare the strategy found by the optimal control theory in a complex molecular system according to the active subspace coupled to the field. The model is the isomerization during a Cope rearrangement of Thiele's ester that is the most stable dimer obtained by the dimerization of methyl-cyclopentadienenylcarboxylate. The crudest partitioning consists in retaining in the active space only the reaction coordinate, coupled to a dissipative bath of harmonic oscillators which are not coupled to the field. The control then fights against dissipation by accelerating the passage across the transition region which is very wide and flat in a Cope reaction. This mechanism has been observed in our previous simulations [Chenel et al., J. Phys. Chem. A 116, 11273 (2012)]. We compare here, the response of the control field when the reaction path is coupled to a second active mode. Constraints on the integrated intensity and on the maximum amplitude of the fields are imposed limiting the control landscape. Then, optimum field from one-dimensional simulation cannot provide a very high yield. Better guess fields based on the two-dimensional model allow the control to exploit different mechanisms providing a high control yield. By coupling the reaction surface to a bath, we confirm the link between the robustness of the field against dissipation and the time spent in the delocalized states above the transition barrier.

A series of 1,4-bis(alkoxycarbonyl)azetidin-2-ones, designed as potential suicide-inhibitors of serine proteases, has been synthesized and evaluated against porcine pancreatic elastase (PPE). The most active compound (K(i)similar to10 muM; reversible inhibitor) was equipped with phenethyloxycarbonyl and benzyloxycarbonyl side-chains at positions N1 and C4, respectively, with the (S)-configuration. H-1 NMR spectroscopic analysis of the reaction mixtures showed that the ester function is preferentially hydrolyzed, in both chemical and enzyme-catalyzed reactions, with regard to the azetidinone and urethane functions. Considering the three potentially sensitive carbonyl functions and the two stereoisomers, ab initio calculations were performed to determine the energetic barriers required to reach the transition state structures of hydrolysis in a model of the enzyme pocket. (C) 2002 Elsevier Science Ltd. All rights reserved.

The Bacillus licheniformis BS3 beta-lactamase catalyzes the hydrolysis of the beta-lactam ring of penicillins, cephalosporins, and related compounds. The production of beta-lactamases is the most common and thoroughly studied cause of antibiotic resistance. Although they escape the hydrolytic activity of the prototypical Staphylococcus aureus beta-lactamase, many cephems are good substrates for a large number of beta-lactamases. However, the introduction of a 7alpha-methoxy substituent, as in cefoxitin, extends their antibacterial spectrum to many cephalosporin-resistant Gram-negative bacteria. The 7alpha-methoxy group selectively reduces the hydrolytic action of many beta-lactamases without having a significant effect on the affinity for the target enzymes, the membrane penicillin-binding proteins. We report here the crystallographic structures of the BS3 enzyme and its acyl-enzyme adduct with cefoxitin at 1.7 A resolution. The comparison of the two structures reveals a covalent acyl-enzyme adduct with perturbed active site geometry, involving a different conformation of the omega-loop that bears the essential catalytic Glu166 residue. This deformation is induced by the cefoxitin side chain whose position is constrained by the presence of the alpha-methoxy group. The hydrolytic water molecule is also removed from the active site by the 7beta-carbonyl of the acyl intermediate. In light of the interactions and steric hindrances in the active site of the structure of the BS3-cefoxitin acyl-enzyme adduct, the crucial role of the conserved Asn132 residue is confirmed and a better understanding of the kinetic results emerges.

A reinvestigation of the roots of Strychnos icaja resulted in the isolation of a new bisindole alkaloid named strychnobaillonine (1) with original C-17–N-1′ and C-23–C-17′ junctions, in addition to sungucine, bisnordihydrotoxiferine, and strychnohexamine (2). Compound 1 showed potent activity against the chloroquine-sensitive 3D7 strain of Plasmodium falciparum in vitro with an IC50 value of 1.1 μM. The structures of the compounds were defined by detailed spectroscopic analyses, especially 1H and 13C NMR, DEPT, HSQC, COSY, NOESY, HMBC, and HRESIMS. The proposed absolute configuration was based on biosynthetic considerations and spectroscopic data (CD, NMR) supported by molecular modeling.

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 host–guest interactions play a very important role in chemical and biological processes. It is therefore important to be able to characterize these complexes. Electrospray mass spectrometry can be used to characterize the complex formation. It provides information on the mass and the charge of these ionic complexes. In this article, we show that the use of ab initio and semiempirical calculations, in addition to the results obtained by electrospray mass spectrometry, reveal to be a promising tool for the study of these noncovalent complexes. In this article, host–guest complexes formed by macropolycyclic polyammonium host molecules and dicarboxylic acids are studied.

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.

Novel coumarinic derivatives were synthesized and tested for their inhibitory potency toward α-CT and HLE. Cycloalkyl esters and amides were found to be essentially inactive on both enzymes. On the opposite, aromatic esters strongly inactivated α-CT whereas HLE was less efficiently inhibited with dichlorophenyl ester derivatives (k(inact)/K(I)=4000M-1 s-1 for 36). Representative examples of amide, ester, thioester and ketone derivatives were prepared in order to evaluate the influence of the link between the coumarinic ring and the phenyl side chain. The irreversible inactivation of α-CT by 6-chloromethyl derivatives should be due to alkylation of a histidine residue as suggested by the amino acid analysis of the modified chymotrypsin. Conversely the inhibition of HLE was transient. Intrinsic reactivity of coumarins has been calculated using a model of a nucleophilic reaction between the ligand and the couple methanol-water. From this calculation, it appears that differences in the inhibitory potency expressed by these molecules cannot only be explained by differences in the reactivity of the lactonic carbonyl group toward the nucleophilic attack. Copyright (C) 2000 Elsevier Science Ltd.

Most of the time, the definitions of minima, saddle points or more generally order p (p=0,…,n) critical points, do not mention the possibility of having zero Hessian eigenvalues. This feature reflects some flatness of the potential energy hypersurface in a special eigendirection which is not often taken into account. Thus, the definitions of critical points are revisited in a more general framework within this context. The concepts of bifurcation points, branching points, and valley ridge inflection points are investigated. New definitions based on the mathematical formulation of the reaction path are given and some of their properties are outlined.

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

Piperazine derivatives have been identified as new antidiabetic compounds. Structure-activity relationship studies in a series of 1-benzyl-4-alkyl-2-(4',5'-dihydro-1'H-imidazol-2'-yl)piperazines resulted in the identification of 1-methyl-4-(2', 4'-dichlorobenzyl)-2-(4',5'-dihydro-1'H-imidazol-2'-yl)piperazine, PMS 812 (S-21663), as a highly potent antidiabetic agent on a rat model of diabetes, mediated by an important increase of insulin secretion independently of alpha2 adrenoceptor blockage. These studies were extended to find additional compounds in these series with improved properties. In such a way, substitution of both piperazine N atoms was first optimized by using various alkyl, branched or not, and benzyl groups. Second, some modifications of the imidazoline ring and its replacement by isosteric heterocycles were carried out, proceeding from PMS 812, to evaluate their influence on the antidiabetic activity. The importance of the distance between the imidazoline ring and the piperazine skeleton was studied third. Finally, the influence of the N-benzyl moiety was also analyzed compared to a direct N-phenyl substitution. The pharmacological evaluation was performed in vivo using glucose tolerance tests on a rat model of type II diabetes. The most active compounds were 1,4-diisopropyl-2-(4', 5'-dihydro-1'H-imidazol-2'-yl)piperazine (41a), PMS 847 (S-22068), and 1,4-diisobutyl-2-(4',5'-dihydro-1'H-imidazol-2'-yl)piperazine (41b), PMS 889 (S-22575), which strongly improved glucose tolerance without any side event or hypoglycemic effect. More particularly, PMS 847 proved to be as potent after po (100 micromol/kg) as after ip administration and appears as a good candidate for clinical investigations.

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

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.

This review explores the potential of quantum chemistry to help understand complex biochemical reactions such as enzyme catalysis. Starting from a historical background, the article introduces the reader to the great diversity of problems than can be dealt with in the framework of quantum chemistry.

As starting points to the stepwise access to the corresponding [5]radialene, the unsaturated esters 14a and 18a have been prepared. These compounds have been isolated along with their isomers 14b and 18b, resulting from an intracyclic double-bond migration. Moreover a subsequent base-catalyzed process mediated the total isomerization of these mixtures to the latter more stable compounds 14b and 18b. The energy contents of the various compounds, and the corresponding tri- and tetrasubstituted higher homologues 19 and 20, have been calculated at the ab initio level, using several minimal as well as extended basis sets, and the observed experimental results rationalized.

In the continuation of our investigations on the structure of platelet-activating factor (PAF)-receptor, 25 additional 2-substituted 1,4-bis-(poly- and mono methoxybenzoyl)-piperazines were synthesized and their in vitro biological activities measured. Substituent at position 2 is representative of the classical balance lipophilicity/hydrophilicity, i.e. alkyl, phenylalkyl, alkoxy and polyalkoxy groups. A potent PAF-induced platelet aggregation inhibitory activity measured in PRP medium is obtained with 5c , IC 50 = 6 × 10 −8 M, which displaces the [ 3 H]PAF from platelet membrane with an EC 50 = 6 × 10 −8 M, and compound 4 presents an EC 50 of 3 × 10 −8 M. Examination of structure-activity relationships shows that molecules bearing a hydrophilic or slightly hydrophobic appendix in position-2 are still potent; their IC 50 being included between 10 −6 and 10 −7 M. After quantitative analysis, it seems that in PRP medium, the role of serum albumin must be taken into account instead of a pure hydrophobic interaction of the appendix Z into the receptor. The role of the methoxy groups in producing a potent antagonistic activity is demonstrated by syntheses of several 2-octylpiperazine analogs. These specific features will be quatitatively analysed in the following related publication (part 3).

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.

Assuming that bicyclic β-lactams endowed with high conformational adaptability should more easily form acyl-enzyme complexes with PBP2a than the traditional antibiotics, we have prepared a series of bis-2-oxo-azetidinyl macrocycles as potential inhibitors. The compounds are formally "head-head" (HH) cyclodimers of 1-(ω-alkenoyl)-3-(S)- (ω′-alkenoylamino)-2-azetidinones, with various lengths of the alkene chains, obtained by two successive metathesis reactions using the Grubbs catalyst. All compounds behave as acylating inhibitors of PBP2a and one β-lactam (5c), embedded into the largest ring (32 atoms), features an activity close to that of Ceftobiprole. Conformational analyses, theoretical reactivity models and docking experiments in PBP2a cavity allow to propose a novel pharmacophore, i.e. the 3-(S)-acylamino-1-acyl-2-azetidinone ring, with the syn-conformation of the imide function, associated to a flexible macrocycle favoring the opening of the active site. © 2013 Elsevier Masson SAS. All rights reserved.

International audience; In this work, we present optimal control calculations in a dissipative. environment TO this end, the auxiliary density matrix, method describing the dissipative. quantum dynamics is combined. With,optimal Control theory. The resulting approach, which is nonperturbative in the laser system interaction, is applied to model the control; of Cope's isomerization of the methyl-cyclopentadienylcarboxylate dimer, described as the motion along a one-dimensional reaction path. The construction of the reaction path model as well as the dipole moments: required for the laser interaction are obtained from DFT quantum chemistry calculations. As a main result: we show that the proposed methodology, which includes the environment at the design stage of the control, leads to control fields which can react on dissipative effects during the dynamics and lead to an increased control objective, as compared to control fields obtained Without dissipation. The chosen example is analyzed in detail, and the physical mechanisms of the control under dissipation are elucidated.

Objectives: Our aim was to unravel the inactivation pathway of the class A β-lactamase produced by Bacillus licheniformis BS3 (BS3) by clavulanate. Methods: The interaction between clavulanate and BS3 was studied by X-ray crystallography, pre-steady-state kinetics and mass spectrometry. Results: The analysis of the X-ray structure of the complex yielded by the reaction between clavulanate and BS3 indicates that the transient inactivated form, namely the cis-trans enamine complex, is hydrolysed to an ethane-imine ester covalently linked to the active site serine and a pentan-3-one-5-ol acid. It is the first time that this mechanism has been observed in an inactivated β-lactamase. Furthermore, the ionic interactions made by the carboxylic group of pentan-3-one-5-ol may provide an understanding of the decarboxylation process of the trans-enamine observed in the non-productive complex observed for the interaction between clavulanate and SHV-1 and Mycobacterium tuberculosis β-lactamase (Mtu). Conclusions: This work provides a comprehensive clavulanate hydrolysis pathway accounting for the observed acyl-enzyme structures of class A β-lactamase/clavulanate adducts. Fil: Power, Pablo. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Departamento de Microbiología, Inmunología y Biotecnología. Cátedra de Microbiología; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay; Argentina Fil: Mercuri, Paola. Université de Liège; Bélgica Fil: Herman, Raphaël. Université de Liège; Bélgica Fil: Kerff, Frédéric. Université de Liège; Bélgica Fil: Gutkind, Gabriel Osvaldo. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay; Argentina. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Departamento de Microbiología, Inmunología y Biotecnología. Cátedra de Microbiología; Argentina Fil: Dive, Georges. Université de Liège; Bélgica Fil: Galleni, Moreno. Université de Liège; Bélgica Fil: Charlier, Paulette. Université de Liège; Bélgica Fil: Sauvage, Eric. Université de Liège; Bélgica

Oxidative cross-coupling reactions of substituted o-aminophenols were catalyzed by a commercial laccase to produce non-symmetrically substituted phenoxazinones for the first time. Identification by (1)H-, (13)C- and (31)P-NMR, and by HPLC-PDA and HPLC-MS/MS of exclusively two kinds of substituted phenoxazinones out of four potential heterocyclic frameworks was confirmed by a DFT study. The redox-properties of the substrates, their relative rates of conversion and the rigid docking of selected substrates led to a revisited mechanistic pathway for phenoxazinones biosynthesis. Our suggestions concern both the first formal two-electron oxidation by laccase and the first intermolecular 1,4-conjugated addition which secures the observed regioselectivity.

In this paper, we describe the isolation and structural determination of 2,7-dihydroxyapogeissoschizine, a new alkaloid from the root bark of Strychnos gossweileri. Elucidation of its structure is based mainly on 1D and 2D NMR studies; its conformation was optimized by energy minimization. This type of skeleton is related to geissoschizine but with the notable diffrence that the 1 and 17 positions are joined giving an additional fused ring. Such a seven-membered ring has ,to our knowledge, only been observed in apogeissoschizine, obtained after chemical tratment of two alkaloids ( geissospermine and geissoschizine). 2,7-dihydroxyapogeissoschizine is therefore, the first natural product possessing this skeleton. According to a preliminary test, this new alkaloid shows low toxicity to B16 melanoma cells, but not for non-cancer 3T3 fibroblasts cultured in vitro.THese results have to be confirmed by further tests.

The total number of possible retrosynthetic bisections of C(60) leads to nine different isometric C(30) fragments. These molecules include five chiral units, four of which derive from partitions corresponding to four distinct "Coupes du Roi". The energies, curvatures, and homodesmotic stabilization energies of the C(30) fragments are evaluated at the ab initio 6-31G level.

As potential inhibitors of penicillin-binding proteins (PBPs), we focused our research on the synthesis of non-traditional 1,3-bridged β-lactams embedded into macrocycles. We synthesized 12- to 22-membered bicyclic β-lactams by the ring-closing metathesis (RCM) of bis-I-alkenyl-3(S)- aminoazetidinone precursors. The reactivity of 1,3-bridged β-lactams was estimated by the determination of the energy barrier of a concerted nucleophilic attack and lactam ring-opening process by using ab initio calculations. The results predicted that 16-membered cycles should be more reactive. Biochemical evaluations against R39 DD-peptidase and two resistant PBPs, namely, PBP2a and PBP5, revealed the inhibition effect of compound 4 d, which featured a 16-membered bridge and the N-tert-butyloxycarbonyl chain at the C3 position of the β-lactam ring. Surprisingly, the corresponding bicycle, 12 d, with the PhOCH 2CO side chain at C3 was inactive. Reaction models of the R39 active site gave a new insight into the geometric requirements of the conformation of potential ligands and their steric hindrance; this could help in the design of new compounds. Bridging inhibition: A series of 12- to 22-membered bicyclic bridged β-lactams were synthesized with the aim of developing new inhibitors of penicillin-binding proteins and feature a planar amide function and no carboxy group (see picture; Boc=tert-butyloxycarbonyl). © 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.