Synthesis of Novel Nitro-Halogenated Aryl-Himachalene Sesquiterpenes from Atlas Cedar Oil Components: Characterization, DFT Studies, and Molecular Docking Analysis against Various Isolated Smooth Muscles.

We report the synthesis of two novel halogenated nitro-arylhimachalene derivatives: 2-bromo-3,5,5,9-tetramethyl-1-nitro-6,7,8,9-tetrahydro-5H-benzo[7]annulene (bromo-nitro-arylhimachalene) and 2-chloro-3,5,5,9-tetramethyl-1,4-dinitro-6,7,8,9-tetrahydro-5H-benzo[7]annulene (chloro-dinitro-arylhimachalene). These compounds were derived from arylhimachalene, an important sesquiterpene component of Atlas cedar essential oil, via a two-step halogenation and nitration process. Characterization was performed using 1H and 13C NMR spectrometry, complemented by X-ray structural analysis. Quantum chemical calculations employing density functional theory (DFT) with the Becke3-Lee-Yang-parr (B3LYP) functional and a 6-31++G(d,p) basis set were conducted. The optimized geometries of the synthesized compounds were consistent with X-ray structure data. Frontier molecular orbitals and molecular electrostatic potential (MEP) profiles were identified and discussed. DFT reactivity indices provided insights into the compounds' behaviors. Moreover, Hirshfeld surface and 2D fingerprint analyses revealed significant intermolecular interactions within the crystal structures, predominantly H-H and H-O contacts. Molecular docking studies demonstrate strong binding affinities of the synthesized compounds to the active site of protein 7B2W, suggesting potential therapeutic applications against various isolated smooth muscles and neurotransmitters.

Novel Hydrazono-2-Iminothiazolidin-4-Ones Based on a Monoterpenic Skeleton as Potential Antitumor Agents: Synthesis, DFT Studies, in†Vitro Cytotoxicity, Apoptosis Inducing Properties and Molecular Docking.

A series of novel 2-iminothiazolidin-4-one analogs have been synthesized from limonaketone, and structurally characterized by HR-MS, 1 H-NMR and 13 C-NMR spectroscopy techniques, and the structure of compound 4 was elucidated by XRD. The newly synthesized products were biologically evaluated in vitro for their cytotoxic activity against human cancer cell lines HT-1080, A549, and MCF-7. Thiazolidinones 9 and 10 were the most active compounds in HT-1080 cell lines (IC50 =15.85±1.75 and 16.13±1.55 µM, respectively). The apoptosis induction of the derivatives 9 and 10 were studied using annexin V staining, caspase-3/7 activity and cell cycle analysis. Compound 10 showed the highest ability of apoptosis induction and caspase-3/7 activation associated with S-phase growth arrest in HT-1080. Meanwhile, compound 9 has a moderate apoptotic effect and G0/G1-phase arrest in the after-mentioned cell. The molecular docking suggested that compounds 9 and 10 formed stable ligand-caspase-3 complexes. Besides, the presence of phenyl moiety in ligand 10 is responsible for the enhancement of the caspase-3 activation by the apparition of two additional hydrogen bonds with Cys163 and Gln161amino acids.

Antiproliferative and apoptotic activity of new indazole derivatives as potential anticancer agents.

To develop potent and selective anticancer agents, a series of novel polysubstituted indazoles was synthesized and evaluated for their in vitro antiproliferative and apoptotic activities against two selected human cancer cell lines (A2780 and A549). Several compounds showed an interesting antiproliferative activity, with IC50 values ranging from 0.64 to 17 µM against both cell lines. The most active indazoles were then tested in different pharmacological dilution conditions, adding five new cell lines (A2780, A549, IMR32, MDA-MB-231, and T47D) as targets, confirming their antiproliferative activity. Furthermore, selected compounds were able to trigger apoptosis to a significant extent and to cause, in part, a block of cells in the S phase of the cell cycle, with a concomitant decrease of cells in the G2/M and/or G0/G1 phases and the generation of hypodiploid peaks. However, molecule 7d caused a great increase of cells in G2/M and the appearance of polyploid cells. Altogether, our results suggest a good pharmacological activity for our selected polysubstituted indazoles, which are suggestive of a preferential mechanism of action as cell cycle-specific antimetabolites or as an inhibitor of enzyme activities involved in DNA synthesis, except for 7d, which, on the contrary, seems to have a mechanism involving the microtubule system.

Dilithium manganese(II) catena-tetrakis(polyphosphate), Li2Mn(PO3)4.

The poly-phosphate Li2Mn(PO3)4 was synthesized and its structure characterized from powder diffraction data by Averbuch-Pouchot & Durif [J. Appl. Cryst. (1972), 5, 307-308]. These authors showed that the structure of this phosphate is isotypic to that of Li2Cd(PO3)4, as confirmed by the present work. The structure is built from infinite zigzag polyphosphate chains, [(PO3)(-)] n , extending along [010]. These polyphosphate chains are connected by sharing vertices with MnO6 octa-hedra (site symmetry .m.) and Li2O7 polyhedra, which form also chains parallel to [010]. Adjacent chains are linked by common vertices of polyhedra in such a way as to form porous layers parallel to (100). The three-dimensional framework delimits empty channels extending along [010].

Potassium trinickel(II) orthophosphate diphosphate, KNi3(PO4)P2O7.

The structure of the title compound is characterized by the presence of two different anions, (PO4)(3-) and (P2O7)(4-) with an eclipsed conformation. The crystal structure consists of edge-sharing [NiO6] octa-hedra forming an [Ni3O14] chain running parallel to [001]. Adjacent chains are connected through edges and apices to PO4 and P2O7 groups in such a way as to build a three-dimensional host lattice. The resulting framework presents inter-secting tunnels running along [010] and [101] in which the 11-coordinated potassium cation is located. The crystal structure of this new phosphate probably represents a new structural type.

Hexane-1,6-di-ammonium hexa-fluoro-silicate.

The asymmetric unit of the title organic-inorganic molecular salt, C6H18N2 (2+)·SiF6 (2-), consists of one anion and one cation together with half of each of two cations and two anions located on inversion centres. The SiF6 (2-) octa-hedral anions are arranged to form sheets parallel to (011), which are linked into a three-dimensional network by the organic cations through N-H⋯F hydrogen bonds.

Butane-1,4-di-ammonium hexa-fluoro-silicate.

The title compound, [NH3(CH2)4NH3](2+)·SiF6 (2-), is a hybrid built from an organic butane-1,4-di-ammonium dication linked to a hexa-fluoro-silicate mineral anion. Both ions posses inversion symmetry. In the anion the Si atom is located on an inversion center, while in the cation the center of inversion is situated at the mid-point of the central -CH2-CH2- bond. The Si atom is surrounded by six F atoms, forming a slightly distorted SiF6 (2-) octa-hedron. These octa-hedra are linked to the organic cations through N-H⋯F hydrogen bonds, forming a three-dimensional network.

Crystal structure of N-(1-allyl-3-chloro-4-eth-oxy-1H-indazol-5-yl)-4-meth-oxybenzene-sulfonamide.

In the title compound, C19H20ClN3O4S, the benzene ring is inclined to the indazole ring system (r.m.s. deviation = 0.014 Å) by 65.07 (8)°. The allyl and eth-oxy groups are almost normal to the indazole ring, as indicated by the respective torsion angles [N-N-C-C = 111.6 (2) and C-C-O-C = -88.1 (2)°]. In the crystal, mol-ecules are connected by N-H⋯N hydrogen bonds, forming helical chains propagating along [010]. The chains are linked by C-H⋯O hydrogen bonds, forming a three-dimensional network.

Crystal structure of N-(1-allyl-3-chloro-1H-indazol-5-yl)-4-methyl-benzene-sulfonamide.

The 3-chloro-1H-indazole system in the title mol-ecule, C17H16ClN3O2S, is almost planar, with the largest deviation from the mean plane being 0.029 (2) Šfor one of the N atoms. This system is nearly perpendicular to the allyl chain, as indicated by the C-C-N-N torsion angle of -90.1 (6)° between them. The allyl group is split into two fragments, the major component has a site occupancy of 0.579 (7). The indazole system makes a dihedral angle of 47.53 (10)° with the plane through the benzene ring. In the crystal, mol-ecules are connected by N-H⋯O and C-H⋯O hydrogen bonds, forming a three-dimensional network.

Crystal structure of N-(3-chloro-1-methyl-1H-indazol-5-yl)-4-meth-oxy-benzene-sulfonamide.

In the title compound, C15H14ClN3O3S, the dihedral angle between the planes of the indazole ring system (r.m.s. deviation = 0.007 Å) and the benzene ring is 89.05 (7)°. The meth-oxy C atom deviates from its attached ring by 0.196 (3) Å. In the crystal, inversion dimers linked by pairs of N-H⋯O hydrogen bonds generate R 2 (2)(8) loops. The dimers are connected into [010] chains by C-H⋯O inter-actions.

Crystal structure of (5-methyl-imidazo[1,2-a]pyridin-2-yl)methanol.

In the title compound, C9H10N2O, the imidazo[1,2-a]pyridine moiety is approximately planar (r.m.s. deviation = 0.024 Å). The methanol group is nearly perpendicular to its mean plane as indicated by the C-C-C-O and N-C-C-O torsion angles of 80.04 (16) and -96.30 (17)°, respectively. In the crystal, mol-ecules are linked by O-H⋯N hydrogen bonds, forming inversion dimers with an R (2) 2(10) ring motif. The dimers are liked via C-H⋯O hydrogen bonds, enclosing R (2) 2(10) ring motifs and forming ribbons along [201]. The ribbons are linked via a number of π-π inter-actions [centroid-centroid distances vary from 3.4819 (8) to 3.7212 (8) Å], forming a three-dimensional structure.

1-(4-Methyl-phenyl-sulfon-yl)-5,6-di-nitro-1H-indazole.

In the title compound, C14H10N4O6S, the indazole ring system is almost perpendicular to the tosyl ring, as indicated by the dihedral angle of 89.40 (9)° between their planes. The dihedral angles between the indazole system and the nitro groups are 57.0 (3) and 31.9 (3)°. In the crystal, mol-ecules are linked by C-H⋯O inter-actions, forming chains running along [100].

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.

N-(1-Allyl-3-chloro-4-eth-oxy-1H-indazol-5-yl)-4-methyl-benzene-sulfonamide.

In the title compound, C19H20ClN3O3S, the benzene ring is inclined to the indazole ring system by 51.23 (8)°. In the crystal, mol-ecules are linked by pairs of N-H⋯O hydrogen bonds, forming inversion dimers which stack in columns parallel to [011]. The atoms in the allyl group are disordered over two sets of sites with an occupancy ratio of 0.624 (8):0.376 (8).

N-(3-Chloro-4-eth-oxy-1-methyl-1H-indazol-5-yl)-4-meth-oxy-benzene-sulfonamide.

The indazole ring system of the title compound, C17H18ClN3O4S, is almost planar (r.m.s. deviation = 0.0113 Å) and forms dihedral angles of 32.22 (8) and 57.5 (3)° with the benzene ring and the mean plane through the 4-eth-oxy group, respectively. In the crystal, mol-ecules are connected by pairs of N-H⋯O hydrogen bonds into inversion dimers, which are further linked by π-π inter-actions between the diazole rings [inter-centroid distance = 3.4946 (11) Å], forming chains parallel to [101].

3-Methyl-sulfanyl-5-phenyl-1,2,4-triazine.

In the mol-ecule of the title compound, C10H9N3S, the dihedral angle between the triazine and phenyl rings is 11.77 (7)°. In the crystal, mol-ecules are linked by π-π stacking inter-actions [centroid-centroid distances = 3.7359 (3) and 3.7944 (4) Å], forming layers parallel to the bc plane.

Crystal structure of 2-(4-methyl-benzyl-idene)malono-nitrile.

The mol-ecule of the title compound, C11H8N2, is approximately planar (r.m.s.deviation for all non-H atoms = 0.023 Å). The malono-nitrile C-C-C angle is 113.54 (13)°. In the crystal, mol-ecules stack head-to-tail along [010]. There are no significant inter-molecular inter-actions present.

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.