Synthesis, crystal structure investigation and computational approach to discover potential hydrazide derivatives as a potent inhibitor of cyclooxygenase-2 enzyme.

This study reports the synthesis of two new hydrazide derivatives, namely, (E)-N'-(4- bromobenzylidene)-2-(4-isobutylphenyl)propanehydrazide (4a) and (E)-N'-benzylidene-2-(4-isobutylphenyl)propanehydrazide (4b), respectively. The compounds were synthesized by the reaction of benzaldehyde with Ibuprofen acid hydrazide. Their structures were confirmed by X-ray crystallography. To try to do a more detailed investigation, computational studies including Hirshfeld surface analyses, energy frameworks, density functional theory (DFT) optimizations, frontier orbital analyses, molecular electrostatic potential analyses, and natural bond orbital analyses of the studied compounds are performed. Moreover, molecular docking and dynamics simulations of complexes of the compounds with the cyclooxygenase-2 (COX-2) enzyme were performed to determine the anti-inflammatory potential of the compounds. These analyses predicted the compounds to show maximum chemical interactions and be dynamically stable during simulation time. Furthermore, estimation of binding free energies confirmed the high binding affinity of the compounds for the COX-2 enzyme.

Synthesis, crystal structure, and a molecular modeling approach to identify effective antiviral hydrazide derivative against the main protease of SARS-CoV-2.

In the fall of 2019, a new type of coronavirus took place in Wuhan city, China, and rapidly spread across the world and urges the scientific community to develop antiviral therapeutic agents. In our effort we have synthesized a new hydrazide derivative, (E)-N'-(1-(4-bromophenyl)ethylidene)-2-(6-methoxynaphthalen-2-yl)propanehydrazide for this purpose because of its potential inhibitory proprieties. The asymmetric unit of the title molecule consists of two independent molecules differing noticeably in conformation. In the crystal, the independent molecules are linked by N-H···O and C-H···O hydrogen bonds and C-H···π(ring) interactions into helical chains extending along the b-axis direction. The chains are further joined by additional C-H···π(ring) interactions into the full 3-D structure. To obtain a structure-activity relationship, the DFT-NBO analysis is performed to study the intrinsic electronic properties of the title compound. Molecular modeling studies were also conducted to examine the binding affinity of the compound for the SARS-CoV-2 main protease enzyme and to determine intermolecular binding interactions. The compound revealed a stable binding mode at the enzyme active pocket with a binding energy value of -8.1 kcal/mol. Further, stable dynamics were revealed for the enzyme-compound complex and reported highly favorable binding energies. The net MMGBSA binding energy of the complex is -37.41 kcal/mol while the net MMPBSA binding energy is -40.5 kcal/mol. Overall, the compound disclosed the strongest bond of ing the main protease enzyme and might be a good lead for further structural optimization.

3,6-Di-chloro-9-(prop-2-yn-1-yl)-9H-carbazole.

The tricyclic aromatic ring system of the title compound, C15H9Cl2N, is essentially planar (r.m.s. deviation = 0.002 Å). The two Cl atoms lie slightly out of the plane of the carbazole ring system, with the C-Cl bonds forming angles of 1.23 (8) and 1.14 (8)° with the plane. The acetylene group has a syn orientation with respect to the ring system. In the crystal, no weak hydrogen bonds nor any π-π stacking inter-actions are observed.

4-Chloro-N'-[(3Z)-2-oxo-2,3-di-hydro-1H-indol-3-yl-idene]benzohydrazide.

In the title compound, C15H10ClN3O2, the benzene ring is slightly twisted out of the plane of the 2,3-di-hydro-1H-indole ring system (r.m.s. deviation = 0.007 Å), forming a dihedral angle of 7.4 (3)°. An intra-molecular N-H⋯O hydrogen bond forms a six-membered ring. In the crystal, mol-ecules are linked via N-H⋯O and C-H⋯O hydrogen bonds, forming layers alternately perpendicular to [011] and [0-11].

(2E)-2-(1,3-Benzo-thia-zol-2-yl)-3-(di-methyl-amino)-prop-2-ene-nitrile.

The mol-ecular conformation of title compound, C12H11N3S, is almost planar [maximum deviation = 0.063 (2) Å]; an intra-molecular C-H⋯N hydrogen bond is noted. In the crystal, mol-ecules inter-act with each other via π-π stacking inter-actions between thia-zole rings [centroid-centroid distance = 3.7475 (9) Å] and methyl-H⋯π(C6) inter-actions, forming columns along the a axis.

N-(2-Hy-droxy-phen-yl)-4-methyl-benzene-sulfonamide.

In the title compound, C13H13NO3S, the dihedral angle between the benzene rings is 64.15 (7)° and the C-S-N-C torsion angle is -57.18 (12)°. An intra-molecular N-H⋯O hydrogen bond closes an S(5) ring. In the crystal, O-H⋯O hydrogen bonds link the mol-ecules into C(8) chains propagating in [100]. Weak C-H⋯π inter-actions are also observed.

Crystal structure of N-[4-amino-5-cyano-6-(methyl-sulfan-yl)pyridin-2-yl]-2-(cyclo-hexyl-sulfan-yl)acetamide.

In the title mol-ecule, C15H20N4OS2, the acetamido fragment is nearly coplanar with the pyridyl ring [C-N-C-C torsion angle = -4.1 (2)°], while the cyclo-hexyl-sulfanyl portion protrudes from this plane [N-C-C-S torsion angle = -40.8 (6)°]. In the crystal, alternating pairwise N-H⋯O and N-H⋯N hydrogen bonds across inversion centres form chains along [101], which are associated into stepped layers via offset π-π stacking between pyridyl rings [centroid-centroid distance = 3.566 (1) Å]. The cyclo-hexyl group and the two atoms of the S-C bond attached to it are disordered over two sets of sites with site-occupancy factors of 0.8845 (18) and 0.1155 (18).

Crystal structure of 2-[(E)-2-(2-chloro-benzyl-idene)hydrazin-1-yl]-4-phenyl-1,3-thia-zole.

The asymmetric unit of the title compound, C16H12ClN3S, contains two independent mol-ecules whose conformations differ primarily in the orientations of the phenyl and chloro-benzene rings with respect to the thia-zole ring. In the first mol-ecule, the dihedral angles are 3.0 (1) and 9.2 (1)°, respectively, for the phenyl ring and the chloro-benzene ring, while in the second mol-ecule, the corresponding angles are 18.6 (1) and 23.4 (1)°. In the crystal, the two independent mol-ecules are associated via complementary N-H⋯N hydrogen bonds into a dimer. These dimers are associated through weak C-H⋯Cl and C-H⋯S inter-actions into supra-molecular chains propagating along the a-axis direction.

Crystal structure of ethyl 2-({[(4Z)-3,5-dioxo-1-phenyl-pyrazolidin-4-yl-idene]meth-yl}amino)-acetate.

The title compound, C14H15N3O4, is nearly planar, the dihedral angle between the planes of the phenyl and pyrazolidine rings being 1.13 (7) Å, and that between the plane of the pyrazolidine ring and the mean plane of the side chain [C-N-C-C(=O)-O; r.m.s. deviation = 0.024 Å] being 2.52 (7)°. This is due in large part to the presence of the intra-molecular N-H⋯O and C-H⋯O hydrogen bonds. In the crystal, pairwise N-H⋯O hydrogen bonds form inversion dimers, which are further associated into layers, lying very close to plane (-120), via pairwise C-H⋯O hydrogen bonds. The layers are then weakly connected through C-H⋯O hydrogen bonds, forming a three-dimensional structure.

Crystal structure of 4,6-di-amino-2-sulfanyl-idene-1,2-di-hydro-pyridine-3-carbo-nitrile.

The title compound, C6H6N4S, crystallizes with two independent mol-ecules, A and B, in the asymmetric unit. Both independent mol-ecules are almost planar [maximum deviations of 0.068 (6) Šin mol-ecule A and 0.079 (6) Šin mol-ecule B]. In the crystal, mol-ecules A and B are linked by N-H⋯S, N-H⋯N and C-H⋯S hydrogen bonds, forming a three-dimensional network.

Crystal structure of 2-[12-methyl-14-phenyl-10,13,14,16-tetra-aza-tetra-cyclo[7.7.0.0(2,7).0(11,15)]hexa-deca-1(16),2,4,6,9,11(15),12-heptaen-8-yl-idene]propandi-nitrile.

In the title mol-ecule, C22H12N6, the fused tetracyclic core shows a small lengthwise twist as indicated by the dihedral of 2.7 (2)° between the outer rings. In the crystal, mol-ecules stack along the b-axis direction via offset π-stacking [centroid-centroid distances = 3.5282 (13) and 3.5597 (14) Å] with the stacks weakly associated through C-H⋯N hydrogen bonds. The phenyl ring is rotationally disordered over two orientations with an occupancy ratio of 0.516 (4):0.484 (4).

Crystal structure of (E)-4-{[2-(2,4-di-nitro-phen-yl)hydrazin-1-yl-idene]meth-yl}-3-methyl-1-phenyl-5-(1H-pyrrol-1-yl)-1H-pyrazole.

The title compound, C21H17N7O4, is in an 'extended' conformation aided by an intra-molecular N-H⋯O hydrogen bond. The pyrazole ring makes dihedral angles of 29.17 (6), 65.47 (4) and 9.91 (7)°, respectively, with the phenyl, pyrrole and benzene rings. In the crystal, mol-ecules are connected by pairs of N-H⋯O and C-H⋯O hydrogen bonds, forming inversion dimers which associate into ribbons running along the b axis through complementary C-H⋯O inter-actions.

Crystal structure of 4-((1E)-1-{(2Z)-2-[4-(4-bromo-phen-yl)-3-phenyl-2,3-di-hydro-1,3-thia-zol-2-yl-idene]hydrazin-1-yl-idene}eth-yl)phenol hemihydrate.

In the title compound, C23H18BrN3OS·0.5H2O, the bromo-phenyl, phenyl and phenol rings make dihedral angles of 46.5 (1), 66.78 (8) and 15.4 (2)°, respectively, with the mean squares plane of the thia-zol-idene ring. In the crystal, the lattice water mol-ecule is hydrogen bonded to the phenol group and makes a weaker O-H⋯N connection to an inversion-related mol-ecule, forming a ring while weak pairwise C-H⋯S inter-actions involving inversion-related mol-ecules form a second ring. Both these motifs result in the formation of two-dimensional networks lying parallel to (10-1).

Crystal structure of 3-methyl-1-phenyl-5-(1H-pyrrol-1-yl)-1H-pyrazole-4-carbaldehyde.

In the title compound, C15H13N3O, the pyrrolyl and phenyl rings make dihedral angles of 58.99 (5) and 34.95 (5)°, respectively, with the central pyrazole ring. In the crystal, weak, pairwise C-H⋯O inter-actions across centers of symmetry form dimers, which are further associated into corrugated sheets running approximately parallel to (100) via weak C-H⋯N inter-actions.

Crystal structure of ethyl (2Z)-2-cyano-3-[(3-methyl-1-phenyl-1H-pyrazol-5-yl)amino]-prop-2-enoate.

The title compound, C16H16N4O2, crystallizes with two mol-ecules in the asymmetric unit, one of which shows disorder of the acetate group over two sets of sites in a 0.799 (2):0.201 (2) ratio. The phenyl group has a similar but opposite sense of twist relative to the pyrazole ring in the two mol-ecules, as indicated by the syn N-N-Car-Car (ar = aromatic) torsion angles of 39.7 (2) and -36.9 (2)°. Each mol-ecule features an intra-molecular N-H⋯O hydrogen bond, which closes an S(6) ring. In the crystal, C-H⋯O and C-H⋯N inter-actions direct the packing into a layered structure parallel to (110).

Crystal structure of 5-(4,5-di-hydro-1H-imidazol-2-yl)-3-methyl-1-phenyl-1H-pyrazolo-[3,4-b]pyrazin-6-amine.

In the title compound, C15H15N7, the phenyl ring is inclined by 19.86 (5)° to the mean plane of the pyrazolo-[3,4-b]pyrazine core. In the crystal, N-H⋯N and C-H⋯N hydrogen bonds form [010] chains, which stack via π-π inter-actions [centroid-centroid distance between the pyrazole rings = 3.4322 (7) Å].

Crystal structure of (E)-N-{[3-methyl-1-phenyl-5-(1H-pyrrol-1-yl)-1H-pyrazol-4-yl]methyl-idene}hydroxyl-amine.

The title compound, C15H14N4O, crystallizes with two mol-ecules in the asymmetric unit with similar conformations (r.m.s. overlay fit for the 20 non-H atoms = 0.175 Å). In the first mol-ecule, the dihedral angles between the planes of the central pyrazole ring and the pendant phenyl and pyrrole rings are 42.69 (8) and 51.88 (6)°, respectively, with corresponding angles of 54.49 (7) and 49.61 (9)°, respectively, in the second mol-ecule. In the crystal, the two mol-ecules, together with their inversion-symmetry counterparts, are linked into tetra-mers by O-H⋯N hydrogen bonds. The tetra-mers form layers parallel to (211) through pairwise C-H⋯π inter-actions.

1-{[(Z)-Cyclo-pentyl-idene]amino}-3-phenyl-thio-urea.

The sample of the title compound, C12H15N3S, chosen for study consisted of triclinic crystals twinned by a 180° rotation about the a axis. The five-membered ring adopts a twisted conformation. The dihedral angle between the phenyl ring and the mean plane of the thio-urea unit is 78.22 (8)°. In the crystal, molecules are linked via pairs of N-H⋯S hydrogen bonds forming inversion dimers.

4-Chloro-N'-[(E)-2-chloro-benzyl-idene]benzohydrazide monohydrate.

The title compound, C14H10Cl2N2O·H2O, has a nearly planar extended conformation [C-N-N-C = -173.66 (15)°]. The dihedral angle between the aromatic rings is 4.6 (2)°. The water mol-ecules alternate with benzohydrazide mol-ecules in chains formed by O-H⋯O hydrogen bonds which run parallel to the a axis. These chains are linked to neighboring chains through N-H⋯O and C-H⋯O inter-actions, forming a layer parallel to (001).

4-Phenyl-1,2,4-tri-aza-spiro-[4.4]non-1-ene-3-thione.

In the title compound, C12H13N3S, the 4,5-di-hydro-3H-1,2,4-triazole system is nearly planar [maximum deviation = 0.014 (2) Å], while the cyclo-pentane ring adopts a half-chair conformation. The dihedral angle between the mean plane of the 4,5-di-hydro-3H-1,2,4-triazole-3-thione ring and the phenyl ring is 85.49 (14)°, with the S atom 0.046 (1) Šout of the former plane. The crystal structure is stabilized only by van der Waals inter-actions. The investigated crystal was found to be a non-merohedral two-component twin by a 180° rotation about c*, with a refined value of the minor twin fraction of 0.12203 (18).