Guanidine dicycloamine-based analogs: green chemistry synthesis, biological investigation, and molecular docking studies as promising antibacterial and antiglycation leads.

Dicyandiamide (DCD) reacted with amino acids 1a-f to produce biguanides 2 and 4 and guanidine pyrazolones 3, 5, 6, 7, and 8, according to the reaction. DCD exhibited the following reactions: imidodicarbonimidicdiamide 9, diazocan-2-ylguanidine 10, methyl biguanidylthion 11, N-carbamothioylimidodicarbonimidicdiamide 12, 2-guanidinebenzoimidazole 13a, 2-guanidinylbenzoxazole 13b, and 2-guanidinylbenzothiazol 13c. These reactions were triggered by 6-amino caproic acid, thioacetamide, thiourea, o-aminophenol, o-aminothiophenol, and anthranilic acid, respectively. Compound 2 had the least antimicrobial activity, while compound 13c demonstrated the most antibacterial impact against all bacterial strains. Furthermore, in terms of antiglycation efficacy (AGEs), 12, 11, and 7 were the most effective AGE cross-linking inhibitors. Eight and ten, which showed a considerable inhibition on cross-linking AGEs, come next. Compounds 4 and 6 on the other hand have shown the least suppression of AGE production. The most promising antiglycation scaffolds 8, 11, and 12 in the Human serum albumin (HAS) active site were shown to be able to adopt crucial binding interactions with important amino acids based on the results of in silico molecular docking. The most promising antiglycation compounds 8, 11, and 12 were also shown to have better hydrophilicity, acceptable lipophilicity, gastrointestinal tract absorption (GIT), and blood-brain barrier penetration qualities when their physicochemical properties were examined using the egg-boiled method.

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.

Design, synthesis, and molecular docking of novel pyrazole-chalcone analogs of lonazolac as 5-LOX, iNOS and tubulin polymerization inhibitors with potential anticancer and anti-inflammatory activities.

Uncontrolled inflammation predisposes to pleiotropic effects leading to cancer development thanks to promoting all stages of tumorigenesis. Therefore, cancer-associated inflammation has been delegated as the seventh hallmark of cancer. Thus, raging the war against both inflammation and cancer via the innovation of bioactive agents with dual anti-inflammatory and anticancer activities is a necessity. Herein, a novel series of pyrazole-chalcone analogs of Lonazolac (7a-g and 8a-g) have been synthesized and investigated for their in vitro anticancer activity against four cancer cell lines using the MTT assay method. Among all, hybrid 8g was the most potent against three cancer cell lines, HeLa, HCT-116, and RPMI-822 with IC50 values of 2.41, 2.41, and 3.34 µM, respectively. In contrast, hybrid 8g showed moderate inhibitory activity against MCF-7 with IC50 28.93 µM and with a selectivity profile against MCF-10A (non-cancer cells). Mechanistically, hybrid 8g was the most potent inhibitor against tubulin polymerization (IC50 = 4.77 µM), suggesting tubulin as a molecular target and explaining the observed cytotoxicity of hybrid 8g. This was mirrored by the detected potent pre-G1 apoptosis induction and G2/M cell cycle arrest. Moreover, hybrid8gexhibited selectivity against COX-2 (IC50 = 5.13 µM) more than COX-1 (IC50 = 33.46 µM), indicating that 8g may have lower cardiovascular side effects, but is still not potent as celecoxib (COX-2 IC50 = 0.204 µM, COX-1 = 35.8 µM). Notably, hybrid 8g showed promising inhibitory activity towards 5-LOX (IC50 = 5.88 µM). Finally, the anti-inflammatory activity of hybrid8 g was confirmed by high iNOS and PGE2 inhibitory activities in LPS-stimulated RAW cells with IC50 values of4.93 µM and 10.98 µM, respectively, that accompanied by showingthe most potent inhibition of NO release (70.61 % inhibition rate). Molecular docking studies of hybrid 8g confirmed good correlations with the executed biological results. Furthermore, hybrid 8g had good drug-likeness and suitable physicochemical properties. Taken together, the combined results suggested hybrid8gas a promising orally administered candidate in the journey of repurposing NSAIDs for cancer chemopreventionand treatment.

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.

[Cu(dipicolinoylamide)(NO3)(H2O)] as anti-COVID-19 and antibacterial drug candidate: Design, synthesis, crystal structure, DFT and molecular docking.

For first time the new N-picolinoypicolinlamide was obtained as in situ ligand during the reaction of 2,4,6-ris(2-pyridyl)-,3,5-triazine with aqueous solution of CuNO3·3H2O and formed the corresponding complex [Cu(dipicolinoylamide)(NO3)(H2O)]. The crystal structure of the obtained complex was determined by x-ray structure. The complex crystallizes in space group P21/n, a = 10.2782(9) Å, b = 7.5173(6) Å, c = 17.738(2) Å, α = 90.00°, ß = 91.368(1)°, γ = 90.00°, V = 1370.1(2) Å3, Z = 4. The copper center has a distorted octahedral geometry. DFT calculations show good agreement between theoretical and X-ray data. The Molecular docking studies were executed to consider the nature of binding and binding affinity of the synthesized compounds with the receptor of COVID-19 main protease viral protein (PDB ID: 6lu7), the receptor of gram -ve bacteria (Escherichia coli, PDB ID: 1fj4) and the receptor of gram +ve bacteria (Staphylococcus aureus, PDB ID: 3q8u and Proteus PDB ID: 5i39) and with human DNA. Finally, in silico ADMET predictions was also examined.

Crystal structure of 1H-imidazol-3-ium 2-(1,3-dioxoisoindolin-2-yl)acetate.

The title salt, C3H5N2 (+)·C10H6NO4 (-), was obtained during a study of the co-crystallization of N'-[bis-(1H-imidazol-1-yl)methyl-ene]isonicotinohydrazide with (1,3-dioxoisoindolin-2-yl)acetic acid under aqueous conditions. The 1,3-dioxoisoindolinyl ring system of the anion is essentially planar [maximum deviation = 0.023 (2) Å]. In the crystal, cations and anions are linked via classical N-H⋯O hydrogen bonds and weak C-H⋯O hydrogen bonds, forming a three-dimensional network. Weak C-H⋯π inter-actions and π-π stacking inter-actions [centroid-centroid distances = 3.4728 (13) and 3.7339 (13) Å] also occur in the crystal.

Crystal structure of 9-(3-bromo-5-chloro-2-hydroxy-phen-yl)-10-(2-hy-droxy-eth-yl)-3,3,6,6-tetra-methyl-3,4,6,7,9,10-hexa-hydro-acridine-1,8(2H,5H)-dione.

The title compound C25H29BrClNO4, comprises a 3,3,6,6-tetra-methyl-tetra-hydro-acridine-1,8-dione ring system that carries a hy-droxy-ethyl substituent on the acridine N atom and a 3-bromo-5-chloro-2-hy-droxy-phenyl ring on the central methine C atom of the di-hydro-pyridine ring. The benzene ring is inclined to the acridine ring system at an angle of 89.84 (6)° and this conformation is stabilized by an intra-molecular O-H⋯O hydrogen bond between the hy-droxy substituent on the benzene ring and one of the carbonyl groups of the acridinedione unit. In the crystal, O-H⋯O, C-H⋯O and C-H⋯Br hydrogen bonds combine to stack mol-ecules in inter-connected columns propagating along the a-axis direction.

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 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.

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.