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 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 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.

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).

Methyl 2-((2Z,5Z)-4-oxo-3-phenyl-2-{2-[(1E)-1,2,3,4-tetra-hydro-naphthalen-1-yl-idene]hydrazin-1-yl-idene}-1,3-thia-zolidin-5-yl-idene)acetate.

In the title compound, C22H19N3O3S, the six-membered ring of the 1,2,3,4-tetra-hydro-naphthalene ring system adopts an envelope conformation with the central CH2 C atom as the flap. The mol-ecular conformation is stabilized by an S⋯O contact, forming a pseudo-five-membered ring. In the crystal, mol-ecules are linked via C-H⋯O hydrogen bonds into chains propagating along [102].

2-((1E)-1-{2-[(2Z)-3,4-Diphenyl-2,3-di-hydro-1,3-thia-zol-2-yl-idene]hydrazin-1-yl-idene}eth-yl)pyridin-1-ium bromide monohydrate.

In the title compound, C22H19N4S(+)·Br(-)·H2O, the dihedral angles between the phenyl groups and the mean plane of the thia-zolyl-idene ring are 34.69 (13) and 64.27 (13)°, respectively, while that between the thia-zolyl-idene and pyridinium rings is 14.73 (13)°. In the crystal, zigzag chains of alternating bromide ions and water mol-ecules associate through O-H⋯Br inter-actions run in channels approximately parallel to the b axis. These chains help form parallel chains of cations through N-H⋯O, C-H⋯N and C-H⋯Br hydrogen bonds.

2-((1E)-1-{2-[(2Z)-4-(4-Bromo-phen-yl)-3-phenyl-2,3-di-hydro-1,3-thia-zol-2-yl-idene]hydrazin-1-yl-idene}eth-yl)pyridin-1-ium bromide monohydrate.

In the title hydrated molecular salt, C22H18BrN4S(+)·Br(-)·H2O, the aromatic rings make dihedral angles of 14.20 (12), 34.29 (10) and 68.75 (11)° with the thia-zole ring. In the crystal, mol-ecules are linked into chains running parallel to the a axis by association of the bromide ions and the water mol-ecules of crystallization with the cations via N-H⋯O, O-H⋯Br, C-H⋯N and C-H⋯Br hydrogen-bonding inter-actions. C-H⋯π and C-Br⋯π [3.7426 (11) Å, 161.73 (7)°] inter-actions are also observed, forming infinite chains extending along the b-axis direction.

Bis(2-amino-5-benzyl-3-eth-oxy-carbonyl-4,5,6,7-tetra-hydro-thieno[3,2-c]pyridin-5-ium) bis-(4-meth-oxy-phen-yl)di-phos-phon-ate.

The asymmetric unit of the title salt, 2C17H21N2O2S(+)·C14H14O7P2 (2-), contains half of a centrosymmetric bis-(4-meth-oxy-phen-yl)di-phospho-nate anion and one 2-amino-5-benzyl-3-eth-oxy-carbonyl-4,5,6,7-tetra-hydro-thieno[3,2-c]pyri-din-5-ium cation. In the anion, the O atoms of the di-phospho-nate group are disordered over two positions with equal occupancies. In the cation, the ethyl group is disordered over two orientations with a refined occupancy ratio of 0.753 (5):0.247 (5), and the tetra-hydro-pyridinium ring adopts a distorted half-chair conformation. In the crystal, the ions are linked by C-H⋯O, N-H⋯O and C-H⋯S hydrogen bonds into a three-dimensional network.

N'-[(E)-(Furan-2-yl)methyl-idene]-2-[4-(2-methyl-prop-yl)phen-yl]propano-hydrazide.

In the title mol-ecule, C18H22N2O2, the furan and benzene rings form a dihedral angle of 70.17 (14)°. In the crystal, strong N-H⋯O and weak C-H⋯O hydrogen bonds link the mol-ecules into chains running parallel to [010].

2-Cyclo-heptyl-idene-N-phenyl-hydrazine-carbo-thio-amide.

In the title compound, C14H19N3S, the seven-membered cyclo-heptane ring adopts a chair conformation. An intra-molecular N-H⋯N hydrogen bond [graph-set motif S(5)] is present in the N-N-C-N chain between the ring systems. An intra-molecular C-H⋯S contact also occurs. In the crystal, pairs of mol-ecules form centrosymmetric dimers through N-H⋯S hydrogen bonds [graph-set R 2 (2)(8)]. These dimers are connected by C-H⋯S inter-actions with an R 2 (2)(14) motif.

Methyl (2Z)-2-{(2Z)-3-[(cyclo-pentyl-idene)amino]-4-oxo-2-phenyl-imino-1,3-thia-zol-idin-5-yl-idene}acetate.

In the title compound, C17H17N3O3S, the thia-zole ring is nearly planar [maximum deviation = 0.015 (1) Šfor the ring N atom] and the cyclo-pentane ring has a twist conformation. The mol-ecular conformation is stabilized by a hypervalent inter-action between the S atom and the ester group carbonyl O atom, with an S⋯O distance of 2.7931 (10) Å. In the crystal, C-H⋯O inter-actions generate chains of mol-ecules propagating along [110] and π-π stacking inter-actions [centroid-centroid distance = 3.4677 (7) Å] between the thia-zole rings organize these chains into (001) layers.

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).

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.