1,721,018 research outputs found
Experimental and theoretical charge density study of an antimalarial drug
No full textMalaria, an infection caused by the Plasmodium Falciparum protozoa, is nowadays one of the most lethal parasitic disease. As the Plasmodium protozoon is becoming resistant to quinoline-based molecules, the development of new drugs and the understanding of the key chemical features for their activity and of their mechanism of action is of great importance. In this context, we carried out a thorough analysis on the antimalarial drug dihydroartemisinin (DHA, Figure 1), through the study of its experimental and theoretical charge density (CD) distributions.[1]
The experimental CD has been obtained by a single-crystal X-ray diffraction experiment at T = 100 K on a Bruker SMART APEX II diffractometer equipped with a CCD area detector, while the corresponding theoretical CD has been derived through fully periodic single point DFT calculations at the experimental geometry.
We have identified nucleophilic as well as electrophilic regions of the molecule by analyzing its electrostatic potential and investigated the crystal packing and the change in the CD distribution moving from the isolated molecule to the crystal. Several CD analysis tools, with special emphasis on the Quantum Theory of Atoms in Molecules (QTAIM) [2], have been adopted, with the aim of fully characterize the chemical nature of specific functional groups, such as the peroxide group and the polyether chain.
We have also performed geometry optimizations on deprotonated and radical anion of DHA, the latter being the intermediate species in most of the proposed antimalarial modes of action of the drug.
[1] G. Saleh, R. Soave, L. Lo Presti, R. Destro Chem. Eur. J. 2013, 19, 3490.
[2] R. F. W. Bader Atoms in Molecules: A Quantum Theory Oxford University Press, Oxford, 1990
Physicochemical properties of zwitterionic L- and DL-alanine crystals from their experimental and theoretical charge densities
No full textThe total experimental electron density distributions p(r) of zwitterionic L- and DL-alanine crystals, as derived from extensive sets of X-ray diffracted intensities collected at 23 and 19 K, are compared to gain an insight into the different physical properties of the two related chiral compounds in the solid state and to explore the extent of the p(r) transferability. Relevant parameters that characterize the two crystal forms are obtained, showing differences and similarities in terms of (i) geometric descriptors, (ii) topological indexes, (iii) molecular electrostatic potential Φ(r) distributions, (iv) atomic volumes and charges, (v) molecular electric moments, and (vi) electrostatic interaction energies. To assess the relative stability of the racemate with respect to the pure enantiomer, the crystal lattice energies, as obtained through DFT fully periodic calculations, are also discussed and compared with the experimental sublimation enthalpies after correction for the proton-transfer energies. In-crystal group charges, evaluated with the quantum theory of atoms in molecules, are found to be transferable between the racemic and the pure enantiomer, at variance with group volumes. Similarly, molecular first and third moments are not strictly transferable and indicate that for the zwitterionic alanine molecule the molecular charge distribution in the DL-crystal is more polarized in the c direction by about 10%. By contrast, quantitative agreement is observed for second and fourth moments. Significant differences arise from (1) the crystal packing of the dipole vectors, which are aligned in an antiparallel fashion in the L-crystal, to be compared with a parallel alignment in the racemate, due the polar space group Pna21 of the latter, (2) the strongly attractive electrostatic energy of a homochiral pair in the L-crystal, which is opposed to the corresponding heterochiral pair in the DL-crystal form. The difference between these Ees values amounts to 135-150 kJ mol-1. Despite this, the two crystal forms are predicted as equally thermodynamically favored by the theoretical P-B3LYP estimates of the crystal lattice energies. Finally, the necessity of an upgrading of the dispersion and exchange-repulsion terms currently adopted within the experimental charge density approach to intermolecular interactions is recognized and discussed
On the interplay between CH...O and OH...O interactions in determining crystal packing and molecular conformation : an experimental and theoretical charge density study of the Fungal Secondary Metabolite Austdiol (C12H12O5)
No full textThe total exptl. electron d. r(r), its Laplacian .del.2r(r), the mol. dipole moment, the electrostatic potential j(r), and the intermol. interaction energies have been obtained from an extensive set of single-crystal X-ray diffracted intensities, collected at T= 70(1) K, for the fungal metabolite austdiol (1). The exptl. results have been compared with theor. densities from DFT calcns. on the isolated mol. and with fully periodic calcns. The crystal structure of (1) consists of zigzag ribbons extended along one cell axis and formed by mols. connected by both OH...O and CH...O interactions, while in a perpendicular direction, adjacent mols. are linked by short CH...O intermol. contacts. An extensive, quant. study of all the intra- and intermol. H...O interactions, based not only on geometrical criteria, but also on the topol. anal. of r(r), as well as on the evaluation of the pertinent energetics, allowed us (i) to assess the mutual role of OH...O and CH...O interactions in detg. mol. conformation and crystal packing; (ii) to identify those CH...O contacts which are true hydrogen bonds (HBs); (iii) to det. the relative hydrogen bond strengths. An exptl., quant. evidence is given that CH...O HBs are very similar to the conventional OH...O HBs, albeit generally weaker. The comparison between exptl. and theor. elec. dipole moments indicates that a noticeable charge rearrangement occurs upon crystn. and shows the effects of the mutual cooperation of HBs in the crystal. The total intermol. interaction energies and the electrostatic energy contribution obtained through different theor. methods are reported and compared with the exptl. results. It is found that the new approach proposed by Spackman, based on the use of the promol. charge d. to approx. the penetration contribution to intermol. electrostatic energies, predicts the correct relative electrostatic interaction energies in most of the cases
The fungal metabolite austdiol
No full textThe title compound, (7R,8S)-7,8-dihydroxy-3,7-dimethyl-6-oxo-7,8-dihydro-6H-isochromene-5-carbaldehyde, C12H12O5,
is a trans-vicinal diol. Of the two fused rings, which lie approximately in the same plane, the pyran ring is almost perfectly planar, while the cyclohexenone ring adopts a
slightly distorted half-chair conformation. The crystal packing is dictated by two strong intermolecular O-H···O interactions,
one involving hydroxy and keto groups, the other involving two hydroxy groups. Molecules are linked together through twofold axes, forming zigzag ribbons extended along the a axis
Isothiazoles. Part VIII. Thermal rearrangement to α,β-unsaturated nitriles of cycloadducts from 3-diethylamino-4-(4-methoxyphenyl)-5-vinyl- isothiazole 1,1-dioxide with nitrile oxides and munchnones
No full text3-Diethylamino-4-(4-methoxyphenyl)-5-vinyl-isothiazole 1,1-dioxide was reacted with nitrile oxides and munchnones affording the cycloadducts in good yields. The cycloaddition reaction occurred at the vinyl group exclusively. The cycloadducts undergo pyrolytic transformation into α,β-unsaturated nitriles through the isoxazole- or pyrrole-isothiazoline 1,1-dioxide intermediates
Progress in the Understanding of the Key Pharmacophoric Features of the Antimalarial Drug Dihydroartemisinin: An Experimental and Theoretical Charge Density Study
No full textThe accurate, experimental charge density distribution, rho(r), of the potent antimalarial drug dihydroartemisinin (DHA) has been derived for the first time from single-crystal X-ray diffraction data at T=100(2) K. Gas-phase and solid-state DFT simulations have also been performed to provide a firm basis of comparison with experimental results. The quantum theory of atoms in molecules (QTAIM) has been employed to analyse the 1(r) scalar field, with the aim of classifying and quantifying the key real-space elements responsible for the known pharmacophoric features of DHA. From theconformational perspective, the
bicyclo[3.2.2]nonane system fixes the
three-dimensional arrangement of the
1,2,4-trioxane bearing the active O- O
redox centre. This is the most nucleophilic function in DHA and acts as an important CH···O acceptor. On the
contrary, the rest of the molecular
backbone is almost neutral, in accordance
with the lipophilic character of
the compound. Another remarkable
feature is the C O bond length alternation
along the O-C-O-C polyether chain, due to correlations between pairs of adjacent C O bonds. These bonding features have been related with possible reactivity routes of the alpha- and beta-DHA epimers, namely 1) the base-catalysed hemiacetal breakdown and 2) the peroxide reduction. As a general conclusion, the base-driven
proton transfer has significant nonlocal
effects on the whole polyether chain, whereas DHA reduction is thermodynamically
favourable and invariably leads to a significant weakening (or even breaking) of the O -O bond. The influence of the hemiacetal stereochemistry on the electronic properties of the system has also been considered. Such findings are discussed in the context of the known chemical reactivity of this class of important antimalarial drugs
Looking for structural phase transitions in the colossal magnetoresistive thiospinel FeCr2S4 by a multi-temperature single-crystal X-ray diffraction study
No full textA multi-temperature X-ray diffraction study was performed on the colossal magnetoresistive thiospinel FeCr2S4 to find out if structural phase transitions are associated with the magnetic transitions of the two Fe and Cr sublattices. The temperature dependence of the cell parameters was carefully screened, and the crystal structure was determined at four different temperatures. The present X-ray diffraction experiment, the first performed on a single crystal, confirms that bulk FeCr2S4 is not subject to structural phase transformations in the temperature range 293-23 K. The occurrence of the forbidden (0 0 2) reflection and the non-stoichiometric sample composition are discussed. (c) 2005 Elsevier B.V. All rights reserved
Progress in the understanding of drug-receptor interactions, Part 1 : Experimental charge-density study of an angiotensin II receptor antagonist (C30H30N6O3S) at T=17K
No full textAn experimental study of the electron-density distribution rho(r) in an angiotensin II receptor antagonist 1 has been made on the basis of single-crystal X-ray diffraction data collected at a low temperature. The crystal structure of 1 consists of infinite ribbons in which molecules are connected by an N-H center dot center dot center dot N hydrogen bond and several interactions of the CH center dot center dot center dot O, C-H center dot center dot center dot N, and C-H center dot center dot center dot S type. The molecular conformation, characterized by the syn orientation of a tetrazole and a pyrimidinone ring with respect to a phenyl spacer group, is stabilized by two short S center dot center dot center dot O and S center dot center dot center dot N intramolecular contacts between a substituted thiophene fragment and the other two heterocycles of 1. The electrostatic nature of these teractions is documented. Furthermore, the Laplacian of rho(r) in the plane defined by the sulfur, oxygen, and nitrogen atoms involved in these interactions shows their strongly directional character as the regions of charge concentration on the valence shell of the nitrogen and oxygen atoms directly face the regions of charge depletion on the valence shell of the sulfur atom. All the chemical bonds and the relevant intra- and intermolecular interactions of 1 have been quantitatively described by the topological analysis of rho(r). Simple relationships between the bond path lengths (R-b) and the values of rho at the bond critical points (rho(hcp)) have been obtained for the 28 C-C bonds, the seven N-C bonds, and the four O-C bonds. For the first two classes of bonds the relationship is in the form of a straight line, whose parameters, for the C-C bonds, agree, within experimental uncertainty, with those previously derived in our laboratory from a 19 K X-ray diffraction study of crystals of a different compound. Maps of the molecular electrostatic potential phi(r) derived from the experimental charge density display features that are important for the drug-receptor recognition of 1
Isothiazoles. Part 13: Synthesis of sulfamic esters, [1,2] thiazete S,S-dioxides, benzo[e][1,2]thiazine S,S-dioxides or triazoles by reaction of isothiazole dioxides with sodium azide
No full textThe reaction of sodium azide with 5-substituted 3-diethylamino-4-(4-methoxyphenyl)-isothiazole 1,1 dioxides is presented affording [2-cyano-1-diethylamino-2-(4-methoxyphenyl)-ethylidene]-sulfamic acid derivatives, 3-diethylamino-1,1-dioxo-4-(4-methoxyphenyl)-1,2-dihydro-[1,2]thiazete-4-carbonitrile, 3-diethylamino-7-methoxy-1,1-dioxo-1,4-dihydro-benzo[e][1,2]thiazine-4-carbonitrile or triazole derivatives. The outcome of the reaction strongly depends on C-5 substituent and the correct choice of the reaction conditions allows direction of the reaction towards the formation of the sulfamic acid esters or the [1,2]thiazete carbonitrile or the triazoles in satisfactory yield
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