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.

A Molecule of the Viridomycin Family Originating from a Streptomyces griseus-Related Strain Has the Ability to Solubilize Rock Phosphate and to Inhibit Microbial Growth.

Some soil-borne microorganisms are known to have the ability to solubilize insoluble rock phosphate and this process often involves the excretion of organic acids. In this issue, we describe the characterization of a novel solubilizing mechanism used by a Streptomyces strain related to Streptomyces griseus isolated from Moroccan phosphate mines. This process involves the excretion of a compound belonging to the viridomycin family that was shown to play a major role in the rock phosphate bio weathering process. We propose that the chelation of the positively charged counter ions of phosphate constitutive of rock phosphate by this molecule leads to the destabilization of the structure of rock phosphate. This would result in the solubilization of the negatively charged phosphates, making them available for plant nutrition. Furthermore, this compound was shown to inhibit growth of fungi and Gram positive bacteria, and this antibiotic activity might be due to its strong ability to chelate iron, a metallic ion indispensable for microbial growth. Considering its interesting properties, this metabolite or strains producing it could contribute to the development of sustainable agriculture acting as a novel type of slow release bio-phosphate fertilizer that has also the interesting ability to limit the growth of some common plant pathogens.

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.

Controlled Dimroth Rearrangement in the Suzuki-Miyaura Cross Coupling of Triazolopyridopyrimidines.

Polynitrogen heterocycles are often subject to Dimroth rearrangement which consists of ring opening, bond rotation, and ring closure. In this note, we report a synthesis of two new families of triazolopyridopyrimidines. Successful functionalization via a Suzuki-Miyaura coupling was performed with total control of triazole (Dimroth) isomerization based on the judicious choice of reaction conditions.

New Bioactive Semisynthetic Derivatives of 31-Norlanostenol and Obtusifoliol from Euphorbia officinarum.

Fifteen semisynthetic terpenoid derivatives from the major latex components of Euphorbia officinarum have been evaluated against the insect pest Spodoptera littoralis, two species of protozoan parasites, Trypanosoma cruzi and Leishmania infantum, and also against insect Sf9 and mammalian CHO cells to test their selective cytotoxicity. Our results showed that 40% of the test substances were postingestive toxicants to S. littoralis. All the tested derivatives had cytotoxic effects on insect-derived Sf9 cells, whereas mammalian CHO cells were affected by a lower number of compounds (47%). Furthermore, 87% of the test compounds had antiparasitic effects on both L. infantum and T. cruzi, with some of them being selective parasite toxicants.

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.

Crystal structure of 1-isopropyl-4,7-dimethyl-3-nitro-naphthalene.

The title compound, C15H17NO2, was synthesized from a mixture of α-himachalene (2-methyl-ene-6,6,9-tri-methylbi-cyclo-[5.4.0(1,7)]undec-8-ene) and ß-himachalene (2,6,6,9-tetra-methylbi-cyclo-[5.4.0(1,7)]undeca-1,8-diene), which were isolated from an oil of the Atlas cedar (Cedrus Atlantica). The naphthalene ring system makes dihedral angles of 68.6 (2) and 44.3 (2)°, respectively, with its attached isopropyl C/C/C plane and the nitro group. In the crystal, mol-ecules held together by a C-H⋯O inter-action, forming a chain along [-101].

Crystal structure of (1S,3R,8R,9S,10R)-10-bromo-methyl-2,2-di-chloro-9,10-ep-oxy-3,7,7-tri-methyl-tri-cyclo-[6.4.0.0(1,3)]dodeca-ne.

The title compound, C16H23BrCl2O, was synthesized in 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 the essential oil of the Atlas cedar (cedrus atlantica). The mol-ecule is built up from two fused six- and seven-membered rings, each linked to a three-membered ring. The six-membered ring has a screw-boat conformation, whereas the seven-membered ring displays a twist-boat conformation. The absolute structure was established unambiguously from anomalous dispersion effects.

Crystal structure of (1S,2R,4R,9S,11S,12R)-9α-hy-droxy-4,8-dimethyl-12-[(thio-morpholin-4-yl)meth-yl]-3,14-dioxatri-cyclo-[9.3.0.0(2,4)]tetra-dec-7-en-13-one.

The title compound, C19H29NO4S, was synthesised from 9α-hy-droxy-parthenolide (9α-hy-droxy-4,8-dimethyl-12-methyl-ene-3,14-dioxatri-cyclo-[9.3.0.0(2,4)]tetra-dec-7-en-13-one), which was isolated from the chloro-form extract of the aerial parts of the plant Anvillea radiata. The mol-ecule is built up from two fused five- and ten-membered rings, with an additional ep-oxy ring system and a thio-morpholine group as a substituent. The ten-membered ring adopts an approximate chair-chair conformation, while the thio-morpholine ring displays a chair conformation and the five-membered ring has an envelope conformation, with the C atom closest to the hy-droxy group forming the flap. An intra-molecular O-H⋯N hydrogen bond closes an S(8) ring. The crystal structure features weak C-H⋯O hydrogen-bonding inter-actions, which link the mol-ecules into [010] chains.

Theoretical study of stereoselectivity of the [1 + 2] cycloaddition reaction between (1S,3R,8S)-2,2-dichloro-3,7,7,10-tetramethyltricyclo[6,4,0,0(1.3)]dodec-9-ene and dibromocarbene using density functional theory (DFT) B3LYP/6-31G*(d).

In this work we used density functional theory (DFT) B3LYP/6-31G*(d) to study the stoichiometric reaction between the product (1S,3R,8S)-2,2-dichloro-3,7,7,10-tetramethyltricyclo[6,4,0,0(1.3)]dodec-9-ene (referred to here as P1) and dibromocarbene. We have shown that P1 behaves as a nucleophile, while dibromocarbene behaves as an electrophile; that the chemical potential of dibromocarbene is superior to that of P1 in absolute terms; and that P1 reacts with an equivalent quantity of dibromocarbene to produce two products: (1S,3R,8R,9S,11R)-10,10-dibromo-2,2-dichloro-3,7,7,11-tetramethyltetracyclo[6,5,0,0(1.3),0(9.11)] tridecane (referred to here as P2) and (1S,3R,8R,9R,11S)-10,10-dibromo-2,2-dichloro-3,7,7,11-tetramethyltetracyclo[6,5,0,0(1.3),0(9.11)] tridecane (referred to here as P3). P2 and P3 are formed at the α and ß sides, respectively, of the C2 = C3 double bond of P1. This reaction is exothermic, stereoselective and chemospecific, and is controlled by charge transfer. Regioselectivity of the reaction was interpreted using the Lee-Yang-Parr functional.

Synthesis and biological evaluation of 9α- and 9ß-hydroxyamino-parthenolides as novel anticancer agents.

A series of 9α-hydroxyamino-parthenolides 3-10, 9ß-hydroxyamino-parthenolides 11-13 and 9α-hydroxy-1ß,10α-epoxyamino-parthenolides 15-19 were efficiently synthesized starting from 9α-hydroxyparthenolide 1 and 9ß-hydroxyparthenolide 2, which were isolated from Anvillea radiata. Compounds 1-13 and 15-19 were evaluated for their in vitro anticancer activity by the MTT colorimetric assay against one murine and six human cancer cell lines. This work provides new details about the structural requisites for anticancer activity.

(1R,4R,6S,7R)-5,5-Di-bromo-1,4,8,8-tetra-methyl-tri-cyclo-[5.4.1.0(4,6)]dodecan-12-one.

The title compound, C16H24Br2O, was synthesized from the reaction of ß-himachalene (3,5,5,9-tetra-methyl-2,4a,5,6,7,8-hexa-hydro-1H-benzo-cyclo-heptene), which was isolated from Atlas cedar (Cedrus atlantica). The asymmetric unit contains two independent mol-ecules with similar conformations. Each mol-ecule is built up from two fused seven-membered rings and an additional three-membered ring. In both mol-ecules, one of the seven-membered rings has a chair conformation, whereas the other displays a screw-boat conformation.

9α-Hy-droxy-12-{[4-(4-hy-droxy-phen-yl)piperazin-1-yl]meth-yl}-4,8-dimethyl-3,14-dioxatri-cyclo-[9.3.0.0(2,4)]tetra-dec-7-en-13-one.

The title compound, C25H34N2O5, was synthesized from 9α-hy-droxy-parthenolide (9α-hy-droxy-4,8-dimethyl-12-methylen-3, 14-dioxa-tri-cyclo-[9.3.0.0(2,4)]tetra-dec-7-en-13-one), which in turn was isolated from the chloro-form extract of the aerial parts of Anvillea radiata. The mol-ecule comprises a ten-membered ring fused to a five-membered ring with an additional ep-oxy ring system fused to the ten-membered ring. The five-membered ring also carries a 4-hy-droxy-phenyl-piperazin-1-ylmethyl substituent. The ten-membered ring adopts an approximate chair-chair conformation, while the piperazine ring displays a chair conformation and the five-membered ring shows an envelope conformation with the C atom closest to the hy-droxy group forming the flap. Two C atoms in the phenyl ring and the O atom of the hydroxyl group are disordered over two sites, with an occupancy ratio of 0.53 (5):0.47 (5). An intra-molecular O-H⋯N hydrogen-bond stabilizes the mol-ecular conformation. In the crystal, C-H⋯O hydrogen bonds link the mol-ecules into zigzag chains running along the a-axis direction.

(1S,2R,3S,6S,7R)-3,7,11,11-Tetra-methyl-6,7-epoxybi-cyclo-[5.4.0]undecane-2-ol.

The title compound, C15H26O2, was synthesized 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 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 seven- and six-membered rings each have a twist-boat conformation. In the crystal, O-H⋯O hydrogen bonds link the mol-ecules into zigzag chains running along the b-axis direction.

1-[(1S,6R,7S,9R)-8,8-Di-bromo-5,5,9-tri-methyl-tri-cyclo-[4.4.0.1(7,9)]decan-1-yl]ethanone.

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 asymmetric unit contains two independent mol-ecules with almost identical conformations. Each mol-ecule is built up from two fused six-membered rings, one having a chair conformation and the other a boat conformation, and an additional three-membered ring arising from the reaction of himachalene with di-bromo-carbene. In the crystal, there are no significant intermolecular interactions present. The absolute structure of the title compound was confirmed by resonance scattering.

12-{[4-(4-Bromo-phen-yl)piperazin-1-yl]meth-yl}-9α-hy-droxy-4,8-dimethyl-3,14-dioxatri-cyclo-[9.3.0.0(2,4)]tetra-dec-7-en-13-one.

The title compound, C25H33BrN2O4, was synthesized from 9α-hy-droxy-parthenolide (9α-hy-droxy-4,8-dimethyl-12-methylen-3,14-dioxa-tri-cyclo-[9.3.0.0(2,4)]tetra-dec-7-en-13-one), which was isolated from the chloro-form extract of the aerial parts of Anvillea radiata. The mol-ecule is built up from two fused five- and ten-membered rings with an additional ep-oxy ring system and a bromo-phenyl-piperazine group as a substituent. The ten-membered ring adopts an approximate chair-chair-chair conformation, while the piperazine ring displays a chair conformation and the five-membered ring shows an envelope conformation with the C atom closest to the hy-droxy group forming the flap. An intra-molecular O-H⋯N hydrogen bond stabilizes the mol-ecular conformation. The crystal packing features C-H⋯O hydrogen bonds, which link the mol-ecules into zigzag chains running along the b-axis direction.

(1S,3S,8R,9S,11R)-10,10-Di-bromo-3,7,7,11-tetra-methyl-tetra-cyclo-[6.5.0.0(1,3).0(9,11)]trideca-ne.

The title compound, C17H26Br2, was synthesized 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 the essential oil of the Atlas cedar (Cedrus Atlantica). The asymmetric unit contains two independent mol-ecules with similar conformations. Each mol-ecule is built up from fused six- and seven-membered rings and two appended three-membered rings. In both mol-ecules, the six-membered ring has a screw boat conformation, whereas the seven-membered ring displays a boat conformation. No specific inter-molecular inter-actions were discerned in the crystal packing.

(1S,3R,8R,11S)-11-Bromo-10-bromo-methyl-2,2-di-chloro-3,7,7-tri-methyl-tricyclo-[6.4.0.0(1,3)]dodec-9-ene.

The title compound, C16H22Br2Cl2, was synthesized from ß-him-achalene (3,5,5,9-tetra-methyl-2,4a,5,6,7,8-hexa-hydro-1H-benzo-cyclo-heptene), which was isolated from the essential oil of the Atlas cedar (Cedrus Atlantica). The mol-ecule is built up from fused six- and seven-membered rings and an appended three-membered ring. The six-membered ring has a half-chair conformation, whereas the seven-membered ring displays a chair conformation. The dihedral angle between the two best plane through each ring is 59.5 (2)°. No specific inter-molecular inter-actions were discerned in the crystal packing.