Synthesis, characterization, anticancer evaluation and mechanisms of cytotoxic activity of novel 3-hydroxy-3-pyrrolin-2-ones bearing thenoyl fragment: DNA, BSA interactions and molecular docking study.

In order to make a progress in discovering a new agents for chemotherapy with improved properties and bearing in mind the fact that substituted 3-hydroxy-3-pyrrolin-2-ones belong to a class of biologically active compounds, series of novel 1,5-diaryl-4-(2-thienylcarbonyl)-3-hydroxy-3-pyrrolin-2-ones were synthesized and characterized by spectral (UV-Vis, IR, NMR, ESI-MS), X-ray and elemental analysis. All compounds were examined for their cytotoxic effect on human cancer cell lines HeLa and MDA-MB 231 and normal fibroblasts (MRC-5). Four compounds, 3-hydroxy-1-(p-tolyl)-4-(2-thienylcarbonyl)-5-(4-chlorophenyl)-2,5-dihydro-1H-pyrrol-2-one (D10), 3-hydroxy-1-(3-nitrophenyl)-4-(2-thienylcarbonyl)-5-(4-(benzyloxy)phenyl)-2,5-dihydro-1H-pyrrol-2-one (D13), 3-hydroxy-1-(4-nitrophenyl)-4-(2-thienylcarbonyl)-5-(4-(benzyloxy)phenyl)-2,5-dihydro-1H-pyrrol-2-one (D14), and 3-hydroxy-1-(4-chlorophenyl)-4-(2-thienylcarbonyl)-5-(4-(benzyloxy)phenyl)-2,5-dihydro-1H-pyrrol-2-one (D15), that showed the highest cytotoxicity against malignant cells and the best selectivity towards normal cells were selected for further experiments. Results obtained by investigating mechanisms of cytotoxic activity suggest that selected 3-hydroxy-3-pyrrolin-2-one derivatives in HeLa cells induce apoptosis that is associated with S phase arrest (D13, D15, and D10) or unrelated to cell cycle distribution (D14). Additionally, to better understand their suitability for potential use as anticancer medicaments we studied the interactions between biomacromolecules (DNA or BSA) and D13 and D15. The results indicated that D13 and D15 have great affinity to displace EB from the EB-DNA complex through intercalation [Ksv = (3.7 ±â€¯0.1) and (3.4 ±â€¯0.1) × 103 M-1, respectively], an intercalative mode also confirmed through viscosity measurements. Ka values, obtained as result of fluorescence titration of BSA with D13 and D15 [Ka = (4.2 ±â€¯0.2) and (2.6 ±â€¯0.2) × 105 M, respectively], support the fact that a significant amount of the tested compounds could be transported and distributed through the cells. In addition, by DNA and BSA molecular docking study for D13, D14 and D15 is determined and predicted the binding mode and the interaction region.

Discovery of the Biginelli hybrids as novel caspase-9 activators in apoptotic machines: Lipophilicity, molecular docking study, influence on angiogenesis gene and miR-21 expression levels.

In order to investigate potential therapeutically agents, novel products of Biginelli reaction (4a-l) were synthesized and exposed to cytotoxic and caspase activities, angiogenesis, cell cycle distribution, gene and microRNA expression levels, lipophilicity assessment and docking study. Among the twelve novel compounds (4a-l) evaluated for the cytotoxic activity, five of them (4c, 4d, 4f, 4k and 4l) that showed excellent activity on the tested cell lines (HeLa, LS174 and A549) were selected for further evaluation. Interestingly, compound 4f has up to three times higher selectivity index (SI) towards cancer cells than cisplatin (on HeLa, LS174 and A549 SI = 18.2, 13.5 and 11.2, respectively). The obtained results from cell cycle distribution and caspase activity indicate that tested compounds (4c, 4d, 4f, 4k and 4l) promoted caspase-9 activation, implicated in the intrinsic pathway of apoptosis. Lipophilicity of 4a-l was determinate by using reversed-phase high-performance liquid chromatography.

Charge-density distribution and electrostatic flexibility of ZIF-8 based on high-resolution X-ray diffraction data and periodic calculations.

The electron-density distribution in a prototypical porous coordination polymer ZIF-8 has been obtained in an approach combining high-resolution X-ray diffraction data and Invariom refinement. In addition, the periodic quantum-chemical calculation has been used to describe the theoretical density features of ZIF-8 in the same geometry (m1) and also in a "high-pressure" form of ZIF-8 (m2) characterized by conformational change with respect to the methylimidazolate linker. A thorough comparison of the electronic and electrostatic properties in two limiting structural forms of ZIF-8 proposes additional aspects on diffusion and adsorption processes occurring within the framework. The dimensions of the four-membered (FM) and six-membered (SM) apertures of the ß cage are reliably determined from the total electron-density distribution. The analysis shows that FM in m2 becomes competitive in size to the SM aperture and should be considered for the diffusion of small molecules and cations. Bader's topological analysis (quantum theory of atoms in molecules) shows similar properties of both ZIF-8 forms. On the other hand, analysis of their electrostatic properties reveals tremendous differences. The study suggests exceptional electrostatic flexibility of the ZIF-8 framework, where small conformational changes lead to a significantly different electrostatic potential (EP) distribution, a feature that could be important for the function and dynamics of the ZIF-8 framework. The cavity surface in m1 contains 38 distinct regions with moderately positive, negative, or neutral EP and weakly positive EP in the cavity volume. In contrast to m1, the m2 form displays only two regions of different EP, with the positive one taking the whole cavity surface and the strong negative one localized entirely in the FM apertures. The EP in the cavity volume is also more positive than that in m1. A pronounced influence of the linker reorientation on the EP of the ZIF-8 forms is related to the high symmetry of the system and to an amplification of the electrostatic properties by cooperative effects of the proximally arranged structural fragments.

Synthesis, characterization, and antimicrobial evaluation of a small library of ferrocene-containing acetoacetates and phenyl analogs: the discovery of a potent anticandidal agent.

A library of 16 2-substituted methyl acetoacetates containing ferrocenyl or phenyl units was designed to disclose differences in the antimicrobial activity of ferrocene-containing compounds and their phenyl analogs. Two methyl acetoacetates, whose structures do not contain an aromatic nucleus, were also included in order to probe the inherent activity of the scaffold itself. The acetoacetates were synthesized (low-to-good yields) and fully characterized by spectral (MS, IR, UV-Vis, 1D and 2D NMR) and electrochemical (cyclic voltammetry) techniques. Single-crystal X-ray analysis has been performed for methyl 2-acetyl-2-(ferrocenylmethyl)-5-methylhex-4-enoate. All compounds have demonstrated in vitro antimicrobial activity against six bacterial (three Gram-positive and three Gram-negative) and two fungal strains with minimal inhibitory concentration values of 0.0050-20.6 µmol mL(-1). The most active compound was 2-acetyl-2-(ferrocenylmethyl)-4-methylpent-4-enoate whose activity was comparable to that of nystatin against the yeast Candida albicans. Agglomerative hierarchical clustering statistical analysis of the antimicrobial assay data demonstrated that ferrocene-containing compounds have statistically different and greater antimicrobial activity when compared to their phenyl analogs.

(E)-4-[(2-carbamoylhydrazinylidene)methyl]-3-hydroxy-5-hydroxymethyl-2-methylpyridin-1-ium nitrate.

The title compound, C9H13N4O3(+)·NO3(-), is the first structurally characterized Schiff base derived from semicarbazide and pyridoxal. Unusually for an unsubstituted semicarbazone, the compound adopts a syn conformation, in which the carbonyl O atom is in a cis disposition relative to the azomethine N atom. This arrangement is supported by a pair of hydrogen bonds between the organic cation and the nitrate anion. The cation is essentially planar, with only a hydroxymethyl O atom deviating significantly from the mean plane of the remaining atoms (r.m.s. deviation of the remaining non-H atoms = 0.01 Å). The molecules are linked into flat layers by N-H···O and C-H···O hydrogen bonds. O-H···O hydrogen bonds involving the hydroxymethyl group as a donor interconnect the layers into a three-dimensional structure.

4-[(4-Methyl-phen-yl)sulfan-yl]butan-2-one.

In the title compound, C11H14OS, all non-H atoms are essentially coplanar, with a mean deviation of 0.023 Å. In the crystal, centrosymmetrically related mol-ecules are weakly connected into dimers by pairs of C-H⋯O inter-actions. The dimers are further linked along the a axis by weak C-H⋯π and C-H⋯S inter-actions.

Benzyl 2-(benzylsulfanyl)benzoate.

In the title compound, C(21)H(18)O(2)S, the central aromatic ring makes dihedral angles of 5.86 (12) and 72.02 (6)° with the rings of the terminal O-benzyl and S-benzyl groups, respectively. The dihedral angle between the peripheral phenyl rings is 66.16 (6)°. In the crystal, mol-ecules are linked by pairs of C-H⋯O hydrogen bonds, forming inversion dimers. These dimers are linked via C-H⋯π inter-actions, forming a three-dimensional network.

4-Eth-oxy-3-meth-oxy-benzaldehyde.

In the title compound, C10H12O3, all non-H atoms are approximately coplanar, with an r.m.s. deviation of 0.046 Å. In the crystal, very weak C-H⋯O inter-actions link the mol-ecules into sheets parallel to (101).

A new polymorph of 1-ferrocenyl-3-(3-nitroanilino)propan-1-one.

Recrystallization of the title compound, [Fe(C(5)H(5))(C(14)H(13)N(2)O(3))], from a mixture of n-hexane and dichloromethane gave the new polymorph, denoted (I), which crystallizes in the same space group (P1) as the previously reported structure, denoted (II). The Fe-C distances in (I) range from 2.015 (3) to 2.048 (2) Å and the average value of the C-C bond lengths in the two cyclopentadienyl (Cp) rings is 1.403 (13) Å. As indicated by the smallest C-Cg1-Cg2-C torsion angle of 1.4° (Cg1 and Cg2 are the centroids of the two Cp rings), the orientation of the Cp rings in (I) is more eclipsed than in the case of (II), for which the value was 15.3°. Despite the pronounced conformational similarity between (I) and (II), the formation of self-complementary N-H···O hydrogen-bonded dimers represents the only structural motif common to the two polymorphs. In the extended structure, molecules of (I) utilize C-H···O hydrogen bonds and, unlike (II), an extensive set of intermolecular C-H···π interactions. Fingerprint plots based on Hirshfeld surfaces are used to compare the packing of the two polymorphs.

4-[(2E)-2-(2-Hy-droxy-benzyl-idene)hydrazin-1-yl]benzonitrile.

The asymmetric unit of the title Schiff base, C(14)H(11)N(3)O, contains two independent mol-ecules which have similar conformations. The dihedral angles between the benzene rings are 4.19 (9) and 14.18 (9)° in the two mol-ecules. An intra-molecular O-H⋯N hydrogen bond stabilizes the mol-ecular conformation of each mol-ecules. The crystal packing is dominated by pairs of equivalent N-H⋯N and C-H⋯O hydrogen bonds which arrange the mol-ecules into layers parallel to (-111).

2-(1,3-Dioxoisoindolin-2-yl)acetic acid-N'-[(E)-4-meth-oxy-benzyl-idene]pyridine-4-carbohydrazide (2/1).

In the crystal structure of the title compound, 2C(10)H(7)NO(4)·C(14)H(13)N(3)O(2), the two independent acid mol-ecules are connected through strong O-H⋯N and O-H⋯O hydrogen bonds to the central mol-ecule of the anti-tubercular drug N'-[(E)-4-meth-oxy-benzyl-idene]pyridine-4-carbohydrazide. Two such trimolecular units related by an inversion centre inter-act through a pair of N-H⋯O hydrogen bonds, forming a 3 + 3 mol-ecular aggregate. The dihedral angle between the aromatic rings of the hydrazone mol-ecule is 1.99 (12)°. The crystal packing features weak C-H⋯O and π-π stacking inter-actions, with centroid-centroid distances of 3.8460 (19) and 3.8703 (13) Å.

2-[(Phenyl-carbamo-yl)amino]-butyl N-phenyl-carbamate.

In the title compound, C(18)H(21)N(3)O(3), the terminal phenyl rings make a dihedral angle of 86.3 (5)°. In the crystal, mol-ecules are linked by N-H⋯O hydrogen bonds into chains along [001], forming parallel C(4) and R(1) (2)(6) graph-set motifs.

3-(3-Acetyl-anilino)-1-ferrocenylpropan-1-one.

The title ferrocene-containing Mannich base, [Fe(C(5)H(5))(C(16)H(16)NO(2))], crystallizes with two independent mol-ecules (A and B) in the asymmetric unit. Mol-ecules A and B have similar conformations. The dihedral angles between the best planes of the benzene and substituted cyclo-penta-dienyl rings are 88.59 (9) and 84.39 (10)° in A and B, respectively. In the crystal, the independent mol-ecules form centrosymmetric dimers via corresponding N-H⋯O hydrogen bonds. The dimers further arrange via C-H⋯π and C-H⋯O inter-actions. There are no significant inter-actions between the A and B mol-ecules.

1-Ferrocenyl-3-(2-methyl-anilino)propan-1-one.

In the ferrocene-containing Mannich base, [Fe(C(5)H(5))(C(15)H(16)NO)], the dihedral angle between the mean planes of the benzene ring and the substituted cyclo-penta-dienyl ring is 84.63 (7)°. The conformation of the title compound significantly differs from those found in corresponding m-tolyl-amino and p-tolyl-amino derivatives. In the crystal, C-H⋯O inter-actions connect the mol-ecules into chains, which further inter-act by means of C-H⋯π inter-actions. It is noteworthy that the amino H atom is shielded and is not involved in hydrogen bonding.

3-Anilino-1-ferrocenylpropan-1-one.

In the title ferrocene derivative, [Fe(C(5)H(5))(C(14)H(14)NO)], the dihedral angle between the mean planes of the phenyl ring and the substituted cyclo-penta-dienyl ring is 84.4 (1)°. The mol-ecules are connected into centrosymmetric dimers via N-H⋯O hydrogen bonds. In addition, C-H⋯O and C-H⋯N contacts stabilize the crystal packing.

1-Ferrocenyl-3-(4-methyl-anilino)propan-1-one.

In the title ferrocene derivative, [Fe(C(5)H(5))(C(15)H(16)NO)], the dihedral angle between the best planes of the benzene and the substituted cyclo-penta-dienyl ring is 83.4 (1)°. The presence of a methyl substituent in the para position of the aniline group does not alter the crystal packing compared to that of 3-anilino-1-ferrocenylpropan-1-one [Leka et al. (2012 ▶). Acta Cryst. E68, m229]. The molecules are connected into centro-symmetric dimers via N-H⋯O hydrogen bonds. In addition, C-H⋯O and C-H⋯N contacts stabilize the crystal packing.

1-Ferrocenyl-3-(3-fluoro-anilino)propan-1-one.

The title ferrocene derivative, [Fe(C(5)H(5))(C(14)H(13)FNO)], crystallizes in the same space group with similar unit-cell parameters as the derivatives 3-anilino-1-ferrocenylpropan-1-one [Leka et al. (2012 ▶). Acta Cryst. E68, m229] and 1-ferrocenyl-3-(4-methyl-anilino)propan-1-one [Leka et al. (2012 ▶). Acta Cryst. E68, m230]. The dihedral angle between the best planes of the benzene ring and the substituted cyclo-penta-dienyl ring is 83.4 (1)°. The presence of the electronegative fluoro substituent in the meta position of the aniline group does not alter the crystal packing compared to the other two derivatives. The molecules are connected into centrosymmetric dimers via N-H⋯O hydrogen bonds. In addition, C-H⋯O and C-H⋯N contacts stabilize the crystal packing.

Pyrazolone-type compounds: synthesis and in silico assessment of antiviral potential against key viral proteins of SARS-CoV-2.

Coronavirus outbreak is still a major public health concern. The high mutation ability of SARS-CoV-2 periodically delivers more transmissible and dangerous variants. Hence, the necessity for an efficient and inexpensive antiviral agent is urgent. In this work, pyrazolone-type compounds were synthesised, characterised using spectroscopic methods and theoretical tools, and evaluated in silico against proteins of SARS-CoV-2 responsible for host cell entry and reproduction processes, i.e., spike protein (S), Mpro, and PLpro. Five of twenty compounds are newly synthesised. In addition, the crystal structure of a pyrazolone derivative bearing a vanillin moiety is determined. The obtained in silico results indicate a more favourable binding affinity of pyrazolone analogues towards Mpro, and PLpro in comparison to drugs lopinavir, remdesivir, chloroquine, and favipiravir, while in the case of S protein only lopinavir exerted higher binding affinity. Also, the investigations were performed on ACE2 and the spike RBD-ACE2 complex. The obtained results for these proteins suggest that selected compounds could express antiviral properties by blocking the binding to the host cell and viral spreading, also. Moreover, several derivatives expressed multitarget antiviral action, blocking both binding and reproduction processes. Additionally, in silico ADME/T calculations predicted favourable features of the synthesised compounds, i.e., drug-likeness, oral bioavailability, as well as good pharmacokinetic parameters related to absorption, metabolism, and toxicity. The obtained results imply the great potential of synthesised pyrazolones as multitarget agents against SARS-CoV-2 and represent a valuable background for further in vitro investigations.

Chemoselective synthesis of multifunctional ferrocene-containing derivatives by the cross Rauhut-Currier reaction.

A simple protocol has been developed for the chemoselective synthesis of ferrocene-containing Rauhut-Currier adducts from 1-ferrocenyl-2-nitroethene and vinyl ketones using 20 mol% of triphenylphosphine. Multifunctional ferrocene derivatives were obtained in moderate to high yields (51-92%) by the coupling between the α-position of vinyl ketones and the ß-position of the nitroalkene. The study of the Rauhut-Currier reaction under the described conditions showed that the strong electron-donating group at the ß-position of nitroalkenes plays a significant role in the reaction outcome due to prevention of polymerization and stabilization of the zwitterionic intermediate. Additionally, a preparative synthesis of 4-ferrocenyl-3-methylene-5-nitropentan-2-one was carried out and its synthetic transformations showed easy conversion to other useful building blocks.

Pyrazole Derivatives of Medically Relevant Phenolic Acids: Insight into Antioxidative and Anti-LOX Activity.

BACKGROUND: From the point of view of medicinal chemistry, compounds containing phenolic and pyrazolic moiety are significant since they are often constituents of bioactive compounds. OBJECTIVE: The aims of this study were to synthesize pyrazole derivatives of medically relevant phenolic acids, confirm their structure, and evaluate their antioxidative and anti-LOX activities. METHODS: Phenolic pyrazole derivatives were obtained, starting from esters of medically relevant phenolic acids. The structures of all obtained compounds were determined by NMR and IR spectroscopy, and UV-Vis spectrophotometry. In addition, the single-crystal X-ray diffraction was used. Pyrazole derivatives were tested for their in vitro antioxidative (DPPH assay), and lipoxygenase (LOX) inhibitory activities. Radical quenching mechanism was estimated using DFT and thermodynamic approach, while molecular docking was used to estimate the binding mode within the enzyme. RESULTS: Pyrazole derivatives were obtained in high yields. The crystal structure of a new compound 3e was determined. Pyrazole derivative with catechol moiety 3d exhibited excellent radical scavenging activity, while compound 3b exhibited the best anti-LOX activity. Molecular docking study revealed that there is no direct interaction of any ligand with the active site of LOX-Ib, but pyrazoles 3a-e behave as inhibitors blocking the approach of linoleic acid to the active site. CONCLUSION: In this research, protocatechuic and vanillic acid pyrazole derivatives have been obtained for the first time. In vitro antioxidative assay suggests that pyrazole derivate of protocatechuic acid is a powerful radical scavenger, while anti-LOX assay indicates a pyrazole derivative with 4-hydroxyphenyl moiety.