Novel N-pyrocatechoyl and N-pyrogalloyl hydrazone antioxidants endowed with cytotoxic and antibacterial activity.

Over the years, pharmacological agents bearing antioxidant merits arose as beneficial in the prophylaxis and treatment of various health conditions. Hazardous effects of radical species hyperproduction disrupt normal cell functioning, thus increasing the possibility for the development of various oxidative stress-associated disorders, such as cancer. Contributing to the efforts for efficient antioxidant drug discovery, a thorough in vitro and in silico assessment of antioxidant properties of 14 newly synthesized N-pyrocatechoyl and N-pyrogalloyl hydrazones (N-PYRs) was accomplished. All compounds exhibited excellent antioxidant potency against the 2,2-diphenyl-1-picrylhydrazyl (DPPH) radical. The extensive in silico analysis revealed multiple favorable features of N-PYRs to inactivate harmful radical species, which supported the obtained in vitro results. Also, in silico experiments provided insights into the preferable antioxidant pathways. Prompted by these findings, the cytotoxicity effects and the influence on the redox status of cancer HCT-116 cells and healthy fibroblasts MRC-5 were evaluated. These investigations exposed four analogs exhibiting both cytotoxicity and selectivity toward cancer cells. Furthermore, the frequently uncovered antimicrobial potency of hydrazone-type hybrids encouraged investigations on G+ and G- bacterial strains, which revealed the antibacterial potency of several N-PYRs. These findings highlighted the N-PYRs as excellent antioxidant agents endowed with cytotoxic and antibacterial features.

Antioxidant and cytotoxic activities of selected salicylidene imines: experimental and computational study.

Selected salicylidene imines were evaluated for their antioxidant and cytotoxic potentials. Several of them exerted potent scavenging capacity towards ABTS radical and hydrogen peroxide. The insight into the preferable antioxidative mechanism was reached employing density functional theory. In the absence of free radicals, the SPLET mechanism is dominant in polar surroundings, while HAT is prevailing in a non-polar environment. The results obtained for the reactions of the most active compounds with some medically relevant radicals pointed out competition between HAT and SPLET mechanisms. The assessment of their cytotoxic properties revealed inhibition of ER-a human breast adenocarcinoma cells or estrogen-independent prostate cancer cells. Molecular docking study with the cyclooxygenase (COX) 2 enzyme was performed to examine the most probable bioactive conformations and possible interactions between the tested derivatives and COX-2 binding pocket.

Pyrazolone-type compounds (part II): in vitro and in silico evaluation of antioxidant potential; structure-activity relationship.

The pyrazolone class comprises a variety of hybrid compounds displaying diverse biological actions. Although studied for decades, these compounds are still of interest due to their facile chemical transformations. In our previous work, we presented the synthetic route of functionalised pyrazolone derivatives. The presence of pyrazolone structural motif in many drugs, such as edaravone, prompted us to investigate the antioxidant features of the selected compounds. In this paper, we provide an extensive in vitro and in silico description of the antioxidant properties of selected pyrazolone analogues. The obtained in vitro results revealed their great antiradical potency against the DPPH radical (IC50 values in the 2.6-7.8 µM range), where the best results were obtained for analogues bearing a catechol moiety. Density functional theory (DFT) was used to assess their antioxidant capacity from the thermodynamic aspect. Here, good agreement with in vitro results was achieved. DFT was employed for the prediction of the most preferable radical scavenging pathway, also. In polar solvents, the SPLET mechanism is a favourable scavenging route, whereas in nonpolar solvents the HAT is slightly predominant. Furthermore, antioxidant mechanisms were studied in the presence of relevant reactive oxygen species. The obtained values of the reaction enthalpies with the selected radicals revealed that HAT is slightly prevailing in polar solvents, while the SPLET mechanism is dominant in nonpolar solvents. Regarding the well-known antioxidant features of the drug edaravone, these findings represent valuable data for this pyrazolone class and could be used as the basis for further investigations.

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.

Evaluation of antioxidant and cytotoxic properties of phenolic N-acylhydrazones: structure-activity relationship.

Cancer is still a relentless public health issue. Particularly, colorectal cancer is the third most prevalent cancer in men and the second in women. Moreover, cancer development and growth are associated with various cell disorders, such as oxidative stress and inflammation. The quest for efficient therapeutics is a challenging task, especially when it comes to achieving both cytotoxicity and selectivity. Herein, five series of phenolic N-acylhydrazones were synthesized and evaluated for their antioxidant potency, as well as their influence on HCT-116 and MRC-5 cells viability. Among 40 examined analogues, 20 of them expressed antioxidant activity against the DPPH radical. Furthermore, density functional theory was employed to estimate the antioxidant potency of the selected analogues from the thermodynamical aspect, as well as the preferable free-radical scavenging pathway. Cytotoxicity assay exposed enhanced selectivity of a number of analogues toward cancer cells. The structure-activity analysis revealed the impact of the type and position of the functional groups on both cell viability and selectivity toward cancer cells.

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.

Diethanolamine Pd(II) complexes in bioorganic modeling as model systems of metallopeptidases and soybean lipoxygenase inhibitors.

The reaction of PdCl(2) with diethanolammonium chloride (DEAxHCl), in the molar ratio 1:2, affords the [HDEA](2)[PdCl(4)] complex (1). The hydrolytic activity of the novel Pd(II) complex 1 was tested in reaction with N-acetylated L-histidylglycine dipeptide (AcHis-Gly). Complex 1, as well as earlier prepared trans-[PdCl(2)(DEA)(2)] complex (2), and DEA, as their precursor, were tested for their in vitro free radical scavenging activity. UV absorbance-based enzyme assays were done in order to evaluate their inhibitory activity of soybean lipoxygenase (LOX). Also, assays with superoxide anion radical were done. The scavenging activities of the complexes were measured and compared with those of their precursors and caffeic acid. Complex 2 exhibits the highest antioxidant activity and the highest inhibitory effect against the soybean LOX.

Acetophenone Mannich bases: study of ionic liquid catalysed synthesis and antioxidative potential of products.

Three-component Mannich reaction of acetophenone or 4-iodoacetophenone with a variety of substituted anilines and benzaldehyde, catalysed with diethanolammonium chloroacetate, was performed under mild conditions. Mannich bases (MBs), of which five are new, were obtained in good to excellent yields. All compounds were characterized using elemental analysis, NMR and IR. In addition, detailed experimental and simulated UV-Vis spectral characterization of these compounds is presented here for the first time. In vitro antioxidative potential of synthetized MBs was evaluated using 2,2-diphenyl-1-picryl-hydrazyl radical and density functional theory (DFT) thermodynamical study. It was shown that compounds with anisidine moiety express moderate antioxidative activity. Mechanism of the organocatalysed Mannich reaction was thoroughly inspected by means of DFT. The reaction undergoes the hydrogen bonding-assisted mechanism. Moreover, the proposed rate determining step of the overall reaction is water elimination in the process of iminium ion formation. To the extent of our knowledge, this is the first detailed report on the influence of this type of catalyst on the formation of iminium ion, as a crucial intermediate for the whole reaction.

A new efficient domino approach for the synthesis of pyrazolyl-phthalazine-diones. Antiradical activity of novel phenolic products.

Pyrazolyl-phthalazine-dione derivatives (PPDs) were synthetized in the ionic liquid catalyzed one-pot multicomponent reaction of acetylacetone, 2,3-dihydrophthalazine-1,4-dione, and different aldehydes in moderate to good yields. Six new PPDs were obtained, and the crystal structure of 2-acetyl-1-(4-fluorophenyl)-3-methyl-1H-pyrazolo[1,2-b]phthalazine-5,10-dione (PPD-4) was determined. The most interesting structural features of the novel PPD-4 is the formation of a rather short intermolecular distance between the F atom of one molecule and the midpoint of the neighbouring six-membered heterocyclic ring. This interaction arranges all molecules into parallel supramolecular chains. UV-Vis spectra of all PPDs were acquired and compared to the simulated ones obtained with TD-DFT. All synthetized compounds were subjected to evaluation of their in vitro antioxidative activity using a stable DPPH radical. It was shown that PPD-7, with a catechol motive, is the most active antioxidant, while PPD-9, with two neighbouring methoxy groups to the phenolic OH, exerted a somewhat lower, but significant antioxidative potential. The results of DFT thermodynamical study are in agreement with experimental findings that PPD-7 and PPD-9 should be considered as powerful radical scavengers. In addition, the obtained theoretical results (bond dissociation and proton abstraction energies) specify SPLET as a prevailing radical scavenging mechanism in polar solvents, and HAT in solvents with lower polarity. On the other hand, the obtained reaction enthalpies for inactivation of free radicals suggest competition between HAT and SPLET mechanisms, except in the case of the ˙OH radical in polar solvents, where HAT is labeled as prefered.

Investigation of the antioxidant and radical scavenging activities of some phenolic Schiff bases with different free radicals.

The antioxidant properties of some phenolic Schiff bases in the presence of different reactive particles such as (•)OH, (•)OOH, (CH2=CH-O-O(•)), and (-•)O2 were investigated. The thermodynamic values, ΔH BDE, ΔH IP, and ΔH PA, were used for this purpose. Three possible mechanisms for transfer of hydrogen atom, concerted proton-electron transfer (CPET), single electron transfer followed by proton transfer (SET-PT), and sequential proton loss electron transfer (SPLET) were considered. These mechanisms were tested in solvents of different polarity. On the basis of the obtained results it was shown that SET-PT antioxidant mechanism can be the dominant mechanism when Schiff bases react with radical cation, while SPLET and CPET are competitive mechanisms for radical scavenging of hydroxy radical in all solvents under investigation. Examined Schiff bases react with the peroxy radicals via SPLET mechanism in polar and nonpolar solvents. The superoxide radical anion reacts with these Schiff bases very slowly.

Triethanolammonium acetate as a multifunctional ionic liquid in the palladium-catalyzed green Heck reaction.

An efficient green Heck reaction protocol was performed using a triethanolammonium acetate ionic liquid-palladium(II) catalytic system. The ionic liquid used acts as a reaction medium, base, precatalyst-precursor, and mobile support for the active Pd species. Our experimental investigation indicates that performing the Heck reaction in ionic liquid is superior to the same procedure carried out in triethanolamine. The mechanism of the reaction of triethanolammonium acetate with PdCl(2) was examined using density functional theory (M06 method). It was found that two Pd(II) complexes are formed, one of which acts further as a precatalyst yielding catalytically active Pd(0) complex. The calculated activation energies are in agreement with our experimental findings.

Biological evaluation of mechlorethamine-Pt(II) complex, part II: antimicrobial screening and lox study of the complex and its ligand.

The reaction of K(2)PtCl(4) with anticancer-alkylating agent mechlorethamine hydrochloride (CH(3)NH(C(2)H(4)Cl)(2) x HCl = HN2×HCl), in the molar ratio 1 : 2, affords the complex [H2N2](2)[PtCl(4)]. In vitro antimicrobial and lipoxygenase inhibitory activities of the complex and its precursor were evaluated. Antimicrobial activity of the HN2×HCl and [H2N2](2)[PtCl(4)] complex was investigated against 29 species of microorganisms. Testing is performed by microdilution method. Minimum inhibitory concentration (MIC) and minimum microbicidal concentration (MMC) have been determined. The difference between antimicrobial activity of precursor and corresponding platinum(II) complex is noticed and the activity of the precursor was higher. Tested compounds demonstrated the high and significant antifungal activity and low to moderate antibacterial activity. It was shown that the gram-positive bacteria were more sensitive than the gram-negative. UV absorbance-based enzyme assays were performed with HN2×HCl and [H2N2](2)[PtCl(4)] complex, in order to evaluate their in vitro inhibitory activity of soybean lipoxygenase (LOX), also. Assay with LOX showed significantly greater inhibitory activity of the complex, than the precursor.

Insight into hydrolytic reaction of N-acetylated L-histidylglycine dipeptide with novel mechlorethamine platinum(II) complex. NMR and DFT study of the hydrolytic reaction.

The reaction of K(2)PtCl(4) with the alkylating agent mechlorethamine hydrochloride, at a molar ratio of 1:2, results in the formation of 2-chloro-N-(2-chloroethyl)-N-methylethylammonium-tetrachloridoplatinate(II) complex. The hydrolytic activity of the novel Pt(II) complex was tested in the reaction with N-acetylated L-histidylglycine dipeptide at a molar ratio 1:1. It was shown that the hydrolytic reaction, performed at 60 °C in acidic medium, leads to the regioselective cleavage of the amide bond involving the carboxylic group of histidine. Density functional theory was used to explore the structures of the proposed participants in the hydrolytic reaction.