Explaining the selectivities and the mechanism of [3+2] cycloloaddition reaction between isoalantolactone and diazocyclopropane.

CONTEXT: [3+2] cycloaddition processes between isoalantolactone (ISALL) and diazocyclopropane (DCYP), have been surveyed exercising the MEDT, reactivity indices, reactions, and activation energies, are computed. In an investigation of conceptual DFT indices, DCYP behaves as a nucleophile in this reaction, whereas ISALL acts as an electrophile. This cyclization is stereo-, chemo-, and regiospecific, as demonstrated by the activation and reaction energies, in clear agreement with the experiment's results. The mechanism for this [3+2] cycloaddition is occurring in two steps, according to ELF analysis. METHODS: For the purposes of this investigation, all computations were performed using the Gaussian 09 program. The optimization was completed using Berny's computational gradient optimization approach with the basis set 6-311G(d,p) and wB97XD functional. Frequency computations were utilized to characterize and locate stationary points where the transition phases have just one imaginary frequency and all frequencies for the reactants and products are positive. After evaluating the effect of dichloromethane (DCM) as a reaction solvent, the stationary point optimization was updated using the polarizable continuum model (PCM) developed by the Tomasi team. The electron localization function (ELF) has been examined within the context of topological investigations using Multiwfn software with a 0.05 grid step.

Chemical Composition and In Vitro Antioxidant and Antimicrobial Activities of the Marine Cyanolichen Lichina pygmaea Volatile Compounds.

Volatile compounds from the marine cyanolichen Lichina pygmaea, collected from the Moroccan Atlantic coast, were extracted by hydrodistillation and their putative chemical composition was investigated by gas chromatography coupled to mass spectrometry (GC/MS). Based on the obtained results, Lichina pygmaea volatile compounds (LPVCs) were mainly dominated by sesquiterpenes compounds, where γ-himachalene, ß-himachalene, (2E,4E)-2,4 decadienal and α-himachalene were assumed to be the most abundant constituents, with percentage of 37.51%, 11.71%, 8.59% and 7.62%, respectively. LPVCs depicted significant antimicrobial activity against all tested strains (Staphylococcus aureus CCMM B3, Pseudomonas aeruginosa DSM 50090, Escherichia coli ATCC 8739 and Candida albicans CCMM-L4) with minimum inhibitory concentration (MIC) values within the range of 1.69-13.5 mg/mL. Moreover, this LPVC showed interesting scavenging effects on the 2,2-diphenyl-1-picrylhydrazyl radical with an IC50 of 0.21 mg/mL. LPVCs could be an approving resource with moderate antimicrobial potential and interesting antioxidant activity for cosmetics and pharmaceutical applications.

3D-QSAR, ADME-Tox, and molecular docking of semisynthetic triterpene derivatives as antibacterial and insecticide agents.

In the present work, 27 triterpene derivatives have been subjected to 3D-QSAR, ADME-Tox, and molecular docking for their insecticidal activity. The selected derivatives are previously semi-synthesized based on compounds obtained from Euphorbia resinifera and Euphorbia officinarum latex. The in silico studies were used to predict and to evaluate the antibacterial and insecticidal properties of the 3D structure of triterpene derivatives. The 3D-QSAR models are developed using CoMFA and CoMSIA techniques, and they have showed excellent statistical results (R 2 = 0.99; Q 2 = 0.672; R 2 pred = 0.91 for CoMFA and R 2 = 0.97; Q2 = 0.61; R 2 pred = 0.94 for CoMSIA). The results indicate that the built models are able to describe the relationship between the structure of triterpene derivatives and the pLD50 bioactivity. Based on contour maps obtained from CoMFA and CoMSIA models, 38 new molecules are designed and their pLD50 activities are predicted. The drug-like and ADME-Tox properties of the molecule designed are examined and led to the selection of four molecules (55, 56, 59, 64) as promising antibacterial and insecticidal agents. Compounds 55, 56, 59, and 64 are able to inhibit the MurE (PDB code: 1E8C) and EcR (PDB code: 1R20) proteins involved in the process of antibacterial and insecticidal activities. This hypothesis is confirmed by the implementation of a molecular docking test. This test predicted the most important referential interactions that occur between the structure of triterpene derivatives and the targeted receptors. Among the four docked molecules, three molecules (55, 56, and 59) showed greater stability than the reference molecule 16 inside the MurE and EcR receptors pocket. Therefore, the structure of the three new triterpene derivatives can be adopted as reference for the synthesis of antibacterial drugs and also in the development of insecticides.

Optimization of Insecticidal Triterpene Derivatives by Biomimetic Oxidations with Hydrogen Peroxide and Iodosobenzene Catalyzed by MnIII and FeIII Porphyrin Complexes.

Semisynthetic functionalized triterpenes (4α,14-dimethyl-5α,8α-8,9-epoxycholestan-3ß-yl acetate; 4α,14-dimethyl-5α-cholest-8-ene-3,7,11-trione; 4α,14-dimethyl-5α-cholesta-7,9(11)-dien-3-one and 4α,14-dimethyl-5α-cholest-8-en-3ß-yl acetate), previously prepared from 31-norlanostenol, a natural insecticide isolated from the latex of Euphorbia officinarum, have been subjected to oxidation with hydrogen peroxide (H2 O2 ) and iodosobenzene (PhIO) catalyzed by porphyrin complexes (cytochrome P-450 models) in order to obtain optimized derivatives with high regioselectivity. The main transformations were epoxidation of the double bonds and hydroxylations of non-activated C-H groups and the reaction products were 25-hydroxy-4α,14-dimethyl-5α-cholesta-7,9(11)-dien-3ß-yl acetate (59 %), 25-hydroxy-4α,14-dimethyl-5α-cholest-8-ene-3,7,11-trione (60 %), 4α,14-dimethyl-5α,7ß-7,8-epoxycholest-9(11)-en-3-one (22 %), 8-hydroxy-4α,14-dimethyl-5α-cholest-9(11)-ene-3,7-dione (16 %), 12α-hydroxy-4α,14-dimethyl-5α,7ß-7,8-epoxycholest-9(11)-en-3-one (16 %), and 4α,14-dimethyl-5α,8α-8,9-epoxycholestan-3ß-yl acetate (26 %), respectively. We also investigated the insect (Myzus persicae, Rhopalosiphum padi and Spodoptera littoralis) antifeedant and postingestive effects of these terpenoid derivatives. None of the compounds tested had significant antifeedant effects, however, all were more effective postingestive toxicants on S. littoralis larvae than the natural compound 31-norlanostenol, with 4α,14-dimethyl-5α,8α-8,9-epoxycholestan-3ß-yl acetate being the most active. The study of their structure-activity relationships points out at the importance of C3 and C7 substituents.

Antimicrobial Activity of two Semisynthetic Triterpene Derivatives from Euphorbia officinarum Latex against Fungal and Bacterial Phytopathogens.

This study evaluated the in vitro antimicrobial effect of 3ß-acetoxy-norlup-20-one (1) and 3-chloro-4a,14a-dimethyl-5a-cholest-8-ene (2), triterpene derivatives from Euphorbia officinarum latex against fungal and bacterial phytopathogens. Results showed that although mycelial growth of several strains of Vericillium dahlia, and Fusarium oxysporum fsp. melonis and Penicillium expansum was affected only moderately, the two compounds were able to reduce highly conidia formation and germination, suggesting that they act as fungistatic compounds. Their antibacterial activity was tested against Pseudomonas syringae pv. syringae (Pss), P. syringae pv. tabacci (Pst), Erwinia amylovora (Ea) and Agrobacterium tumefaciens (At) using disc diffusion method. Results showed that compound 2 was more effective in inhibiting the growth of Pss, Pst and Ea than compound 1.

Triterpene derivatives from Euphorbia enhance resistance against Verticillium wilt of tomato.

Oxidation of α-euphorbol and 31-norlanostenol, two triterpenic compounds isolated from the latex of Euphorbia resinifera and Euphorbia officinarum respectively, yielded four products named 3ß-tosyloxy-4α,14α-dimethyl-5α-cholesta-7,9-diene; 4α,14α-dimethyl-5α-cholesta-7,9-dien-3ß-ol; 24-methylen-elemo-lanosta-8,24-dien-3-one and elemo-lanost-8-en-3,11,24-trione. They were evaluated for protection of tomato plants against Verticillium dahliae in a greenhouse. The four semisynthesized products were phytotoxic at higher concentrations as they completely inhibited tomato germination at 100 and 500 µg/ml. However at lower concentrations (10 and 50 µg/ml) germination and root length were not affected. Disease resistance against Verticillium wilt was assessed in tomato plants derived from seeds that germinated in the presence of 10 and 50 µg/ml of the four products. All of them were able to reduce significantly disease severity, with 10 µg/ml being more effective than 50 µg/ml. Reduction of leaf alteration index and of stunting index ranged from 52 to 68% and from 43 to 67%, respectively, while vessel discoloration was reduced by at least 95%. The compounds were also able to elicit H2O2 accumulation before and after fungal inoculation and to significantly enhance peroxidase and polyphenol oxidase activities. These results suggest that the hemisynthetized triterpenes can be used as elicitors of disease resistance.

Crystal structure of (1S,3R,8R,9R,10S)-2,4,6-tris-(2,2-di-chloro-3,7,7,10-tetra-methyl-tri-cyclo-[6.4.0.0(1,3)]dodec-9-yl)cyclo-triboroxane.

The title compound, C48H75B3Cl6O3, was synthesized in two steps from ß-himachalene (3,5,5,9-tetra-methyl-2,4a,5,6,7,8-hexa-hydro-1H-benzo-cyclo-hept-ene), which was isolated from the essential oil of the Atlas cedar (Cedrus Atlantica). The mol-ecule consists of an almost planar cyclo-triboroxane ring [maximum deviation = 0.036 (2) Å] linked to three identical fused ring systems with different conformations. Each of the three attached ring systems is built up from a seven-membered ring to which a six- and a three-membered ring are fused. The three six-membered rings have a twist-boat conformation, whereas the seven-membered rings display boat, chair and twist-boat conformations. The dihedral angles between the central boroxane ring and the mean planes of the attached six-membered rings are 63.67 (18), 54.89 (2) and 56.57 (19)°. The crystal packing is governed only by van der Waals inter-actions.

(1S,3R,8R,10R)-2,2-Di-bromo-3,7,7,10-tetra-methyl-tri-cyclo-[6.4.0.0(1,3)]dodecan-9-one.

The title compound, C16H24Br2O was synthesized by three steps from ß-himachalene (3,5,5,9-tetra-methyl-2,4a,5,6,7,8-hexa-hydro-1H-benzo-cyclo-heptene), which was isolated from essential oil of the Atlas cedar (Cedrus atlantica). The mol-ecule is built up from a seven-membered ring to which a six- and a three-membered ring are fused. The six-membered ring shows a chair conformation. One C atom in the seven-membered ring and two methyl groups attached to the ring are disordered over two sets of sites, with an occupancy ratio of 0.658 (7):0.342 (7).

Antileishmanial and antitrypanosomal activity of triterpene derivatives from latex of two Euphorbia species.

The in vitro activity on Leishmania infantum promastigotes and Trypanosoma cruzi epimastigotes of 25 semisynthetic terpenoid derivatives has been evaluated. These compounds were obtained through chemical modifications of the major components of Euphorbia resinifera (alpha-euphol and alpha-euphorbol) and Euphorbia officinarum (obtusifoliol and 31-norlanosterol). Leishmaniasis and Chagas' disease are major worldwide health problems. The drugs of choice for their treatment are still problematic in both cases, and therefore there is an urgent need to discover new drugs with high activity and low side effects. Natural products have become a key source of new drugs in the last years. The genus Euphorbia has been the subject of abundant phytochemical and pharmacological research because of its potential medical applications, but the antiparasitic effects of derivatives from plants of this genus are still unknown. Our results showed that 76% and 64% of the test compounds had antiparasitic effects on L. infantum and T cruzi, respectively. The different activities on both parasites, especially their moderate effects on mammalian cells, indicate an interesting selective toxicity.

7-Hy-droxy-8-isopropyl-1,1,4a-trimethyl-4a,9,10,10a-tetra-hydro-phenanthren-2(1H)-one.

The title compound, C(20)H(26)O(2), was isolated from a chloro-form extract of Tetra-clinis articulata wood. The mol-ecule contains three fused rings which exhibit different conformations. The non-aromatic oxo-substituted ring has a screw-boat conformation, while the central ring has a half-chair conformation. In the crystal, mol-ecules are linked to each other by inter-molecular O-H⋯O hydrogen bonds involving the carbonyl and hy-droxy groups.

2-Acetyl-3,5,5,9-tetra-methyl-6,7,8,9-tetra-hydro-5H-benzocyclo-hepten-7-one.

The title compound, C(17)H(22)O(2), was semi-synthesized from a mixture of α-atlantone (Z) and α-atlantone (E), which were isolated from the essential oil of the Atlas cedar (cedrus atlantica). The mol-ecule consists of fused six- and seven-membered rings. The seven-membered ring is in a screw-boat conformation.

N-[4-Acetyl-5-methyl-5-(2-p-tolyl-prop-yl)-4,5-dihydro-1,3,4-thia-diazol-2-yl]acetamide.

The title heterocyclic compound, C(17)H(23)N(3)O(2)S, was synthesized from 4-(4-methyl-cyclo-hex-3-en-yl)pent-3-en-2-one, which was isolated from Cedrus atlantica essential oil. The thia-diazole ring adopts a flattened envelope conformation, with the flap sp(3)-hybridized C atom lying 0.259 (1) Šout of the plane of the other four atoms. The screw-related mol-ecules are linked into chains along the b axis by inter-molecular N-H⋯O hydrogen bonds.

N-[4-Acetyl-5-(2-methylprop-1-enyl)-5-(2-p-tolyl-prop-yl)-4,5-dihydro-1,3,4-thia-diazol-2-yl]acetamide.

The title heterocyclic compound, C(20)H(27)N(3)O(2)S, was synthesized from 2-(4-methyl-cyclo-hex-3-en-yl)-6-methyl-hepta-2,5-dien-4-one, which was isolated from the essential oil Cedrus atlantica. The thia-diazole ring is essentially planar [maximum deviation 0.006 (2) Å] and it forms a dihedral angle of 18.08 (9)° with the benzene ring. The dihedral angle between the thia-diazole ring and the acetamide plane is 7.62 (10)°. In the crystal, mol-ecules are linked into chains running along the c axis by inter-molecular N-H⋯O hydrogen bonds.

Bioactive triterpene derivatives from latex of two Euphorbia species.

We have investigated the antifeedant and toxic effects of 23 semisynthetic terpenoid derivatives obtained through chemical modifications of the major components of Euphorbia resinifera (alpha-euphol and alpha-euphorbol) and E. officinarum (obtusifoliol and 31-norlanostenol) latex on several insect species (Spodoptera littoralis, Myzus persicae and Rhopalosiphum padi), their selective cytotoxicity on insect Sf9 and mammalian CHO cells and their phytotoxic effects on Lactuca sativa. The conversions focused mainly on positions 3,7,11, and 24 with several oxidizing agents. A total of 18 compounds affected S. littoralis growth (IGR). Our results support the importance of the C-3 substituent, suggest the involvement of the C-7 substituent and indicate that the C-3 hydroxyl is not essential for the IGR effect. Overall, Sf9 cells were more sensitive to the active compounds than CHO cells. All of these compounds had non selective moderate phytotoxic effects on radicle elongation of L. sativa.

(4aS,10aS)-7-Hydr-oxy-8-isopropyl-1,1,4a-trimethyl-1,2,3,4,4a,9,10,10a-octa-hydro-phenanthrene: a new diterpenoid compound.

The new title diterpenoid compound, C(20)H(30)O, is a natural product isolated from Tetra-clinis articulata wood via chloro-form extraction. The asymmetric unit contains four mol-ecules with the same S,S configuration, deduced from the chemical synthesis. Indeed, an overlay analysis, calculated using structure-matching software, shows that the four mol-ecules can be superimposed. The central ring has a half-chair conformation, whereas the saturated ring displays a chair conformation.

(±)-N-[4-Acetyl-5-methyl-5-(4-methyl-cyclo-hex-3-en-yl)-4,5-dihydro-1,3,4-thia-diazol-2-yl]acetamide.

The new title thiadiazole compound, C(14)H(21)N(3)O(2)S, was semi-synthesized starting from 1-(4-methyl-cyclo-hex-3-en-yl)ethanone, a natural product isolated from Cedrus atlantica essential oil. The stereochemistry has been confirmed by single-crystal X-ray diffraction. The thia-diazo-line ring is roughly planar, although it may be regarded as having a half-chair conformation. The cyclo-hexenyl ring has a half-chair conformation. The most inter-esting feature is the formation of a pseudo-ring formed by four mol-ecules associated through N-H⋯O hydrogen bonds around a fourfold inversion axis, forming an R(4) (4)(28) motif.

N-[4-Acetyl-5-isobutyl-5-(2-p-tolyl-prop-yl)-4,5-dihydro-1,3,4-thia-diazol-2-yl]acetamide ethyl acetate hemisolvate.

The racemic title compound, a new terpenoid, C(20)H(29)N(3)O(2)S·0.5C(4)H(8)O(2), was synthesized from Cedrus Atlantica essential oil. The compound crystallizes with a disordered ethyl acetate solvent mol-ecule. The thia-diazole ring is almost planar, with a maximum deviation from the mean plane of 0.015 (2) Šfor the C atom connected to the isobutyl group and has a puckering amplitude of 0.026 (2) Å. The dihedral angle between the benzene and thia-diazole rings is 18.32 (8)°. The crystal packing involves inter-molecular N-H⋯O hydrogen bonds.

Isolation of new phenylacetylingol derivatives that reactivate HIV-1 latency and a novel spirotriterpenoid from Euphorbia officinarum latex.

Three new, highly functionalized ingol diterpenes, ingol 7,8,12-triacetate 3-phenylacetate (1), ingol 7,8,12-triacetate 3-(4-methoxyphenyl)acetate (2) and 8-methoxyingol 7,12-diacetate 3-phenylacetate (3), together with the novel spirotriterpene, 3S,4S,5R,7S,9R,14R-3,7-dihydroxy-4,14-dimethyl-7[8-->9]-Abeo-cholestan-8-one (4), have been isolated from Euphorbia officinarum latex. Structures were established on the basis of their spectroscopic data, including two-dimensional NMR analysis and NOE experiments. The biological effects of 1-3 on cell cycle and HIV-1 gene transcription were analysed in the Jurkat T cell line. Compound 3 induced cell-cycle arrest and HIV-1-LTR promoter activation and could represent a novel lead compound for the development of therapies against HIV-1 latency.