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The title compound, C17H18ClNO2, was prepared and isolated as a pure diastereoisomer, using column chromatography followed by a succession of fractional crystallizations. Its exact structure was fully identified via 1H NMR and confirmed by X-ray diffraction. It is built up from a central five-membered dihydroisoxazole ring to which a p-chlorophenyl group and a cyclohex-2-enone ring are attached in the 3 and 5 positions. The cyclohex-2-one and isoxazoline rings each exhibit an envelope conformation. The crystal packing features C—H...O, C—H...N and C—H...π interactions, which generate a three-dimensional network.

COVID-19 is a global pandemic caused by infection with the SARS-CoV-2 virus. Remdesivir, a SARS-CoV-2 RNA polymerase inhibitor, is the only drug to have received widespread approval for treatment of COVID-19. The SARS-CoV-2 main protease enzyme (MPro), essential for viral replication and transcription, remains an active target in the search for new treatments. In this study, the ability of novel thiazolyl-indazole derivatives to inhibit MPro is evaluated. These compounds were synthesized via the heterocyclization of phenacyl bromide with (R)-carvone, (R)-pulegone and (R)-menthone thiosemicarbazones. The binding affinity and binding interactions of each compound were evaluated through Schrödinger Glide docking, AMBER molecular dynamics simulations, and MM-GBSA free energy estimation, and these results were compared with similar calculations of MPro binding various 5-mer substrates (VKLQA, VKLQS, VKLQG) and a previously identified MPro tight-binder X77. From these simulations, we can see that binding is driven by residue specific interactions such as π-stacking with His41, and S/π interactions with Met49 and Met165. The compounds were also experimentally evaluated in a MPro biochemical assay and the most potent compound containing a phenylthiazole moiety inhibited protease activity with an IC50 of 92.9 ​μM. This suggests that the phenylthiazole scaffold is a promising candidate for the development of future MPro inhibitors.

Aseries of novel 1,4-disubstituted 1,2,3-triazoles were synthesized from an (R)-carvone terminal alkyne derivative via a Cu (I)-catalyzed azide–alkyne cycloaddition reaction using CuSO4,5H2O as the copper (II) source and sodium ascorbate as a reducing agent which reduces Cu (II) into Cu (I). All the newly synthesized 1,2,3-triazoles 9a–h were fully identified on the basis of their HRMS and NMR spectral data and then evaluated for their cell growth inhibition potential by MTS assay against HT-1080 fibrosarcoma, A-549 lung carcinoma, and two breast adenocarcinoma (MCF-7 and MDA-MB-231) cell lines. Compound 9d showed notable cytotoxic effects against the HT-1080 and MCF-7 cells with IC50 values of 25.77 and 27.89 µM, respectively, while compound 9c displayed significant activity against MCF-7 cells with an IC50 value of 25.03 µM. Density functional calculations at the B3LYP/6-31G* level of theory were used to confirm the high reactivity of the terminal alkyne as a dipolarophile. Quantum calculations were also used to investigate the mechanism of both the uncatalyzed and copper (I)-catalyzed azide–alkyne cycloaddition reaction (CuAAC). The catalyzed reaction gives complete regioselectivity via a stepwise mechanism streamlining experimental observations. The calculated free-energy barriers 4.33 kcal/mol and 29.35 kcal/mol for the 1,4- and 1,5-regioisomers, respectively, explain the marked regioselectivity of the CuAAC reaction.

The new title 4-thiazolidinone derivative, C16H21N3O3S, was obtained from the cyclization reaction of 4-methyl-3-thiosemicarbazone and dimethyl acetylenedicarboxylate (DMAD). The cyclohexylidene ring has an envelope conformation with the stereogenic centre C atom as the flap. Its mean plane makes a dihedral angle of 56.23 (9)° with the thiazolidine ring mean plane. In the crystal, molecules are linked by C—H...O hydrogen bonds forming chains propagating in the [001] direction. Within the chains there are offset π–π interactions between the thiazolidine rings of inversion-related molecules [centroid–centroid distance = 3.703 (1) Å]. The chains are linked by further C—H...O hydrogen bonds, forming slabs parallel to the ac plane.

The title compound, C22H28O3, was prepared by a direct acetylation reaction of naturally occurring totarolenone. The molecule contains three fused rings, which exhibit different conformations. The central ring has a half-chair conformation, while the non-aromatic oxo-substituted ring has a screw-boat conformation. In the crystal, molecules are linked by C—H...O hydrogen bonds and C—H...π interactions, forming sheets parallel to the bc plane. The carbonyl O atoms and the C atom at the 6-position of the cyclohexene ring are each disordered over two sets of sites with major occupancy components of 0.63 (7) and 0.793 (14), respectively.

The title compound, C18H22O4S, an hemisynthetic product, was obtained by the tosylation reaction of the naturally occurring meroterpene p-methoxythymol. The molecule comprises a tetrasubstitued phenyl ring linked to a toluenesulfonate through one of its O atoms. In the crystal, C—H...O and C—H...π interactions link the molecules, forming a three-dimensional network.

The crystal structure and the conformation of the title compound, C22H27N3O7S, were determined from the synthetic pathway and by X-ray analysis. This compound is a new 4-thiazolidinone derivative prepared and isolated as pure product from thiosemicarbazone carvone. The molecule is built up from an oxothiazolidine ring tetrasubstituted by a methoxy–oxoethylidene, a maleate, an oxygen and a cyclohexylidene–hydrazone. The cyclohexylidene ring is statistically disordered over two positions, resulting in an inversion of configuration for the substituted carbon.

The title compound, C16H24Cl2O, was synthesized by treating (1S,3R,8S,9R,10S)-2,2-dichloro-3,7,7,10-tetramethyl-9,10-epoxytricyclo[6.4.0.01,3]dodecane with a concentrated solution of hydrobromic acid. It is built up from three fused rings: a cycloheptane ring, a cyclohexyl ring bearing alkene and hydroxy substituents, and a cyclopropane ring bearing two chlorine atoms. The asymmetric unit contains two molecules linked by an O—H...O hydrogen bond. In the crystal, further O—H...O hydrogen bonds build up an R44(8) cyclic tetramer. One of the molecules presents disorder that affects the seven-membered ring. In both molecules, the six-membered rings display a chair conformation, whereas the seven-membered rings display conformations intermediate between boat and twist-boat for the non-disordered molecule and either a chair or boat and twist-boat for the disordered molecule owing to the disorder. The absolute configuration for both molecules is 1S,3R,8R,9R and was deduced from the chemical pathway and further confirmed by the X-ray structural analysis.

The asymmetric unit of the title compound, C16H24Cl2O2, contains two independent molecules (A and B) which are built from three fused rings, viz. a seven-membered heptane ring, a six-membered cyclohexyl ring bearing a ketone and an alcohol group, and a cyclopropane ring bearing two Cl atoms. In the crystal, the two molecules are linked via two O—H...O hydrogen bonds, forming an A–B dimer with an R22(10) ring motif. The A molecules of these dimers are linked via a C—H...O hydrogen bond, forming chains propagating along the a-axis direction. Both molecules have the same absolute configuration, i.e. 1S,3R,8R,10S, which is based on the synthetic pathway and further confirmed by resonant scattering [Flack parameter = 0.03 (5)].

The title compound, C13H19N3OS, is a new thiazolidin-4-one derivative prepared and isolated as the pure (3aS,6R)-diastereisomer from (R)-thiosemicarbazone pulegone. It crystallized with two independent molecules (A and B) in the asymmetric unit. The compound is composed of a hexhydroindazole ring system (viz. a five-membered dihydropyrazole ring fused to a cyclohexyl ring) with a thiazole-4-one ring system attached to one of the pyrazole N atoms (at position 2). The overall geometry of the two molecules differs slightly, with the mean planes of the pyrazole and thiazole rings being inclined to one another by 10.4 (1)° in molecule A and 0.9 (1)° in molecule B. In the crystal, the A and B molecules are linked via C—H...O hydrogen bonds, forming slabs parallel to the ab plane. There are C—H...π interactions present within the layers, and between the layers, so forming a three-dimensional structure.

There are two independent molecules (A and B) in the asymmetric unit of the title compound, C11H19N3S. In molecule B, two C atoms and the associated H atoms of the cyclohexene ring are disordered over two sets of sites with a site occupancy ratio of 0.649 (7):0.351 (7). The N—N—C—N fragments of the hydrazinecarbothioamide segments of both molecules are not planar, with a torsion angle of −5.8 (3)° for A and 11.6 (3)° for B. The stability of the conformations of both molecules is aided by the formation of intramolecular N—H...N hydrogen bonds. In the crystal, N—H...S hydrogen bonds link like molecules into R22(8) A + B dimers. These dimers are interconnected by additional N—H...S contacts, forming chains along the c-axis direction. The structure was refined as a two-component inversion twin.

The title compound, C16H22Br4, was synthesized in two steps from β-himachalene, which was isolated from essential oil of the Atlas cedar (cedrus atlantica). It is built up from three fused rings, a seven-membered heptane ring, a six-membered cyclohexyl ring bearing both a bromine and a bromomethyl substituent, and a three-membered propane ring bearing two Br atoms. In the crystal, molecules are linked by C—H...Br hydrogen bonds, forming chains propagating along [001]. The absolute configuration was deduced from the chemical pathway and confirmed by resonant scattering [Flack parameter = 0.012 (10)].

The title compound, C11H19N3S, was prepared by the reaction of (R)-pulegone with thiosemicarbazide in acidic medium, using ethanol as solvent. The molecule is built up from fused six and five-membered rings. The six-membered ring adopts a chair conformation, while the five-membered ring displays an envelope conformation with the dimethyl-substituted C atom as the flap. The dihedral angle between the mean planes of the two rings is 20.35 (6)°. In the crystal, molecules are linked by N—H...N and N—H...S hydrogen bonds into chains running parallel to [100].

The title compound, C16H24O3, is built up from three fused rings, a six-membered, a seven-membered and a three-membered ring. The absolute configuration of the title compound was determined as (1R,3S,8R,11R) based on the synthetic pathway. The six-membered ring has an half-chair conformation whereas the seven-membered ring displays a boat conformation. In the cyrstal, C—H...O hydrogen bonds build up a two-dimensional network parallel to (0 0 1). The crystal studied was an inversion twin with a minor twin component of 34%.

The title compound, C16H24Cl2O, is built up from two fused six- and seven-membered rings which bear a dichlorocyclopropane group and an epoxy group, respectively. In the molecule, the six-membered ring adopts an envelope configuration with the C atom linking the epoxy ring at the flap, while the seven-membered ring adopts a boat–sofa conformation.

The title compound, C27H34O2, was hemisynthesized through direct benzoylation of the naturally occurring meroterpene totarol. The central fused six-membered ring has a half-chair conformation, whereas the terminal six-membered ring displays a chair conformation. The dihedral angle between the fused benzene ring and the benzoyl benzene ring is 73.05 (14)°. The S,S chirality of the molecule is consistent with the synthetic pathway, and confirmed by the refinement of the Flack parameter.

The title compound, C16H26O, was synthesized by treating (1S,3S,8R)-3,7,7,10-tetramethyltricyclo[6.4.0.01,3]dodec-9-ene with metachloroperbenzoic acid. The molecule is built up from two fused six- and seven-membered rings. The six-membered ring has a half-chair conformation, whereas the seven-membered ring displays a boat conformation. In the crystal, there are no significant intermolecular interactions present.

The hemisynthesis of the title compound, C22H32O2, was carried out through direct acetylation reaction of the naturally occurring diterpene totarol [systematic name: (4bS,8aS)-4b,8,8-trimethyl-1-propan-2-yl-5,6,7,8a,9,10-hexahydrophenanthren-2-ol]. The molecule is built up from three fused six membered rings, one saturated and two unsaturated. The central unsaturated ring has a half-chair conformation, whereas the other unsaturated ring displays a chair conformation. The absolute configuration is deduced from the chemical pathway. The value of the Hooft parameter [−0.10 (6)] allowed this absolute configuration to be confirmed.

The absolute configuration of the title compound, C16H24O, has been deduced from the chemical pathway. The six-membered ring has a roughly half-chair conformation with the quaternary C atom as the flap. The seven-membered ring displays a chair conformation. In the crystal, there is a weak C—H...O hydrogen bond between the methylene group of the cyclopropane ring and the carbonyl group of a screw-axis-related molecule, which builds up a zigzag-like chain along the b-axis direction.

In the title compound, C13H18O3, the benzene ring is almost perpendicular to the acetoxy plane, making a dihedral angle of 89.33 (11)°. In the crystal, molecules are linked by weak C—H...O hydrogen bonds, forming a zigzag chain along the c-axis direction.

The absolute configuration of the title compound, C16H23BrCl2, has been deduced from the chemical pathway and fully confirmed by refinement of the Flack and Hooft parameters. The six-membered ring adopts a half-chair conformation, whereas the seven-membered ring is a twisted chair. The molecular packing within the crystal is stabilized only by van der Waals interactions.

The title compound, C20H28O2, commonly named Sugiol, is a natural oxygenated diterpene that we have isolated for the first time from a hexane extract of the fruits of Juniperus Oxycedrus L. Its X-ray crystal structure determination confirms an abietane skeleton which was predicted by spectroscopic analysis, mainly by 1H and 13C NMR. The cyclohexane ring adopts a flattened chair conformation, while the cyclohexene ring adopts an envelope conformation. The molecules are linked through O—H...O hydrogen bonds to form a zigzag chain extending parallel to the c axis.

In the search for cancer chemopreventive agents, we have studied the Diels–Alder reaction of trans-communic acid with tetracyanoethylene in the presence of SiO2 as catalyst. The title cycloadduct, C26H30N4O2, was obtained in 75% yield. The molecules are arranged in pairs through O—H...O hydrogen bonds, forming an R22(8) ring motif. Both the fused cyclohexyl rings adopt a chair conformation, whereas the nonfused ring adopts a half-chair conformation.