In Silico Approach: Anti-Tuberculosis Activity of Caespitate in the H37Rv Strain.

Tuberculosis is a highly lethal bacterial disease worldwide caused by Mycobacterium tuberculosis (Mtb). Caespitate is a phytochemical isolated from Helichrysum caespititium, a plant used in African traditional medicine that shows anti-tubercular activity, but its mode of action remains unknown. It is suggested that there are four potential targets in Mtb, specifically in the H37Rv strain: InhA, MabA, and UGM, enzymes involved in the formation of Mtb's cell wall, and PanK, which plays a role in cell growth. Two caespitate conformational structures from DFT conformational analysis in the gas phase (GC) and in solution with DMSO (CS) were selected. Molecular docking calculations, MM/GBSA analysis, and ADME parameter evaluations were performed. The docking results suggest that CS is the preferred caespitate conformation when interacting with PanK and UGM. In both cases, the two intramolecular hydrogen bonds characteristic of caespitate's molecular structure were maintained to achieve the most stable complexes. The MM/GBSA study confirmed that PanK/caespitate and UGM/caespitate were the most stable complexes. Caespitate showed favorable pharmacokinetic characteristics, suggesting rapid absorption, permeability, and high bioavailability. Additionally, it is proposed that caespitate may exhibit antibacterial and antimonial activity. This research lays the foundation for the design of anti-tuberculosis drugs from natural sources, especially by identifying potential drug targets in Mtb.

Information on Gas-Phase Diatomic Molecules from Magnetically Induced Current Densities.

Magnetically induced current densities are different for different types of chemical bonds, and may help highlight some of their characteristics and stress their main differences. The present work considers magnetically induced current densities in the bonds of diatomic molecules bonded by covalent bonds as well as the gas phase molecules of 1:1 ionic compounds, comparing the current strength values and visualizing current density maps. The results show clear-cut differences for the different types of bonds (non-polar covalent, polar covalent, and ionic), and can also be related to the extent of the covalent or ionic character of a bond. For ionic compounds, the results also show relevant differences depending on the charges of the ions and on their electron configuration (including significant effects from the presence of d electrons in the outer shell of the ions). The article presents and analyses the results in detail. It is concluded that the magnetically induced current densities contribute to the description and interpretation of chemical bonding in diatomic molecules. © 2017 Wiley Periodicals, Inc.

Intramolecular Hydrogen Bonding and Conformational Preferences of Arzanol-An Antioxidant Acylphloroglucinol.

Arzanol is a naturally-occurring prenylated acylphloroglucinol isolated from Helichrysum italicum and exhibiting anti-oxidant, antibiotic and antiviral activities. The molecule contains an α-pyrone moiety attached to the phloroglucinol moiety through a methylene bridge. The presence of several hydrogen bond donor or acceptor sites makes intramolecular hydrogen bonding patterns the dominant stabilising factor. Conformers with all the possible different hydrogen bonding patterns were calculated at the HF/6-31G(d,p) and DFT/B3LYP/6-31+G(d,p) levels with fully relaxed geometry in vacuo and in three solvents-chloroform, acetonitrile and water (these levels being chosen to enable comparisons with previous studies on acylphloroglucinols). Calculations in solution were performed with the Polarisable Continuum Model. The results show that the lowest energy conformers have the highest number of stronger intramolecular hydrogen bonds. The influence of intramolecular hydrogen bonding patterns on the other molecular properties is also analysed.

Intramolecular Hydrogen Bonds in Conformers of Quinine and Quinidine: An HF, MP2 and DFT Study.

Quinine is an alkaloid with powerful antimalarial activity, isolated from the bark of Peru's cinchona trees. Quinidine is an erythro diastereoisomer of quinine also exhibiting antimalarial activity. Conformational studies performed so far had never identified conformers with intramolecular hydrogen bonds (IHB). The current study shows the possibility of conformers with an IHB between the quinuclidine and quinoline moieties of these molecules. The study was performed at different levels of theory: Hartree Fock (HF) with the 6-31G(d,p) basis set, Density Functional Theory (DFT) with the B3LYP functional and the 6-31+G(d,p) basis set and Møller-Plesset Perturbation Theory (MP2) with the 6-31+G(d,p) basis set, to confirm the results. The results suggest that the stabilising effect of this IHB is weaker or comparable with respect to the stabilising effect of the preferred mutual orientation of the two moieties. Although the IHB-containing conformers may not be the lowest energy ones, their relative energy is sufficiently low for them to be included among the possible ones responsible for the compounds' antimalarial activity.

A computational study of the effects of different solvents on the characteristics of the intramolecular hydrogen bond in acylphloroglucinols.

Acylphloroglucinols are a broad class of compounds, derivatives from 1,3,5-trihydroxybenzene, and exhibiting a variety of biological activities. They are characterized by the presence of at least one COR group, whose sp(2) O can form an intramolecular hydrogen bond with a neighboring phenolic OH. This H-bond plays dominant roles in determining conformational preferences and energy, and is expected to play significant roles in biological activity mechanisms, which strongly motivates the study of its characteristics in solution. A computational study of a representative number of actual and model structures with different R was carried out in three solvents with different polarities and different types of interactions with solute molecules: water, acetonitrile, and chloroform, utilizing the PCM model. Calculations were mostly performed at the HF/6-31G(d,p) level because of affordability reasons in view of the size and number of the structures considered (the smallest structures were also calculated at MP2/6-31+G(d,p) level). Comparison with the results of a previous study in vacuo shows similar patterns within each medium, pointing to similarities in the influence of relevant geometry factors on the characteristics of the H-bond. The medium appears to have little influence on the parameters of the H-bond. Comparison across media of the energy increase on H-bond removal (an indication of the H-bond strength) is complicated by the greater solvent stabilization of the conformer resulting from H-bond removal, with respect to the one in which the H-bond is present. Several factors, however, would point to a strength not too different from that observed in vacuo.

Five- and six-member bowl-shaped structures from acylphloroglucinols: an ab initio and DFT study.

Molecular structures containing bowl-shaped cavities are interesting for purposes such as hosting molecules or metal ions. Acylphloroglucinols are derivatives of phloroglucinol (1,3,5-trihydroxybenzene) containing a CRO group. A previous study had considered bowl-shaped structures consisting of 3 or 4 identical acylphloroglucinol units linked by methylene bridges, selecting representative R chains and including also a structure with phloroglucinol units. The presence of three 'binding' levels between neighbouring units (consecutive hydrogen bonds in the lower rim, the methylene bridges at intermediate level, and another set of hydrogen bonds in the upper rim) makes these bowls 'deeper' than bowls from other hydroxybenzenes. The current study considers larger bowls, consisting of 5 and 6 identical units, to investigate how the molecular properties change with the increase in the size of the bowl. The monomeric units are the same as in the previous study, and the levels of theory are the same as in the previous study, to enable meaningful comparisons. Like in the previous study, two conformers are considered for each bowl, differing by the orientation of the OH groups in the lower rim. Calculations were performed at the HF/6-31G(d,p) and DFT/B3LYP/6-31+G(d,p) levels with fully relaxed geometry, complemented by single-point MP2/HF/6-31G(d,p) calculations. The results show that the Cnv symmetry (with n being the number of constituting monomers) is maintained for 5-member bowls, while 6-member bowls do not show C6v symmetry but only C2v symmetry. The molecular properties of the calculated bowls are analysed in detail and also compared with the properties of the previously calculated 4- and 5-member bowls. Graphical abstract Bowls built from acylphloroglucinol units have three levels of intermonomer linkages: hydrogen bonds in the bottom rim, methylene bridges at intermediate level, and other hydrogen bonds in the upper rim. They are the deepest bowls that can be built from hydroxybenzene units.

Complexes of arzanol with a Cu2+ ion: a DFT study.

Arzanol (C22H26O7) is a naturally occurring acylphloroglucinol largely responsible for the anti-inflammatory, anti-oxidant, antibiotic and antiviral activities of Helichrysum italicum. Like all acylphloroglucinols, the molecule contains a carboxylic substituent (-COR group); for arzanol, this is a -COCH3 group. The molecule is further characterized by the presence of an α-pyrone ring bonded in meta to -COR through a methylene bridge, and of a prenyl chain bonded to the other meta position. The molecule can form up to three intramolecular hydrogen bonds (IHB) simultaneously, and their presence and patterns are the major stabilizing factors. This work considers complexes of representative conformers of arzanol with a Cu2+ ion, taking into account the different possibilities for the binding of the Cu2+ ion to the electron-density rich sites of the molecule and including simultaneous coordination to two geometrically suitable sites. Calculations were performed at the DFT/B3LYP level, using the 6-31+G(d,p) basis set for the C, O and H atoms and the LANL2DZ pseudopotential for the Cu2+ ion. Interaction energies show preference for simultaneous binding of Cu2+ to two sites. Simultaneous binding to the O of a phenol OH neighboring the prenyl chain and to the π bond of the prenyl chain appears to be the most favorable option, followed by simultaneous binding to the sp2 O of the α-pyrone ring and the O of the phenol OH ortho to -COR on the side of the α-pyrone ring. The charge of the Cu2+ ion is reduced to +1 or slightly less in the complexes, which is consistent with the molecules' antioxidant (reducing) ability. Graphical abstract The copper ion prefers to attach to two sites of the arzanol molecule simultaneously. The arzanol molecule reduces the charge of the copper ion from +2 to +1 by transferring an electron to it; it becomes a radical molecular cation. The distribution of the unpaired electron in the molecule (as highlighted by the spin density maps) depends on the site/s to which the Cu2+ ion binds and on the molecule's conformer.

Computational study of antimalarial pyrazole alkaloids from Newbouldia laevis.

Six pyrazole alkaloids of natural origin (isolated from Newbouldia laevis in DR Congo) that exhibit antimalarial activity-namely withasomnine, newbouldine, and their para-hydroxy and -methoxy derivatives-were investigated theoretically. The nitro derivatives of withasomnine and para-hydroxywithasomnine, which show enhanced antimalarial activity, were also studied in this manner. A thorough conformational study was performed in vacuo and in three solvents (chloroform, acetonitrile, and water) at different levels of theory (HF, DFT/B3LYP, and MP2) using different basis sets. Adducts with explicit water molecules were calculated at the HF level. Due to the rigidity of the pyrazole system and the benzene ring, the only factor that influences the energies of withasomnine and newbouldine is the relative orientation of the two ring systems; two orientations are equally preferred. The para-hydroxy and -methoxy derivatives show a preference for a planar orientation of the OH and OC bonds. The main stabilizing influence on the nitro derivative of para-hydroxywithasomnine is the intramolecular hydrogen bond between the two consecutive functional groups. The calculated adducts show the preferred arrangements of water molecules in the vicinity of the N atoms of the pyrazole system and, for the derivatives, also in the vicinity of the substituents on the benzene ring.

Evaluation of the antiradical activity of hyperjovinol-A utilizing donor-acceptor maps.

Hyperjovinol-A ((2-methyl-1-(2,4,6-trihydroxy-3-(3-hydroxy-3,7-dimethyloct-6-enyl)phen yl)propan-1-one) is an acylated phloroglucinol isolated from Hypericum Jovis and exhibiting good antioxidant activity. The study investigates the compound's antiradical ability on the basis of the electron-donor and electron-acceptor abilities of its conformers, deriving donor and acceptor indexes and mapping them in terms of donor-acceptor maps (DAM). The DAMs of vitamins C and E and of carotene astaxantine are used as comparison references. Calculations were performed at the DFT/BPW91/6-311+G(d,p) level, with optimizations on fully relaxed geometries to obtain the conformers of the neutral molecule in vacuo, and single point calculations to obtain the energies of the cationic and anionic species in vacuo and of the neutral, cationic, and anionic species in water, ethanol, and pentylethanoate. The calculations in solution utilized the polarizable continuum model (PCM). The results indicate that hyperjovinol-A may have better antiradical activity than vitamin C. This is in agreement with experimental results, showing that the antioxidant activity of hyperjovinol-A is comparable with that of the best drugs currently in clinical use. The activity is maintained in solution. The Fukui function f(·) was also calculated for all the conformers of hyperjovinol-A, to identify the regions of highest reactivity.

Investigation of the antioxidant properties of hyperjovinol A through its Cu(II) coordination ability.

Hyperjovinol A (2-methyl-1-(2,4,6-trihydroxy-3-(3-hydroxy-3,7-dimethyloct-6-enyl)phen yl)propan-1-one) is an acylated phloroglucinol isolated from Hypericum Jovis and exhibiting antioxidant properties comparable with those of the most common antioxidant drugs. The study models the compound's antioxidant ability through its ability to coordinate a Cu(2+) ion and reduce it to Cu(+). Complexes with a Cu(2+) ion were calculated for all the low energy and for representative high energy conformers of hyperjovinol A, placing the ion in turn near each of the electron-rich binding sites. The most stable complexes are those in which Cu(2+) binds simultaneously to the O of the OH in the geranyl-type chain (R') and the C═C double bond at the end of R', or to the O of a phenol OH and the O of the OH in R'. The most stable complexes in which Cu(2+) binds only to one site are those in which it binds to the C═C double bond at the end of R' or to the sp(2) O of the COCH(CH3)2 acyl group. Cu(2+) is reduced to Cu(+) in all complexes. Comparisons with corresponding complexes of other molecular structures in which one or more of the structural features of hyperjovinol A are modified attempt to elucidate the role, for the antioxidant ability, of relevant features of hyperjovinol A, like the presence and position of the OH or the C═C double bond in R'. Calculations at the DFT/B3LYP/6-31+G(d,p) level were performed for all the structures considered. Calculations utilizing the LANL2DZ pseudopotential for the Cu(2+) ion were also performed for hyperjovinol A.