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.

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.

Electrochemical characterization and estimation of DNA-binding capacity of a series of novel ferrocene derivatives.

The synthesis of a series of methyl 2-alkyl-5-aryl-4-ferrocenoylpyrrolidine-2-carboxylates has been achieved by [3 + 2] dipolar cycloaddition of azomethine ylides to acryloylferrocene. The electrochemical properties of novel products were examined by cyclic voltammetry (CV) and differential pulse voltammetry (DPV). These techniques revealed the quasi-reversible one-electron oxidation process. The DNA-binding capacity of all the products was also studied using CV and DPV, and significant interactions between synthesized compounds and nucleic acid, mostly of the electrostatic type, were disclosed. DFT calculations and molecular docking tests were carried out to gain a more exhaustive insight into the interactions of the obtained products with nucleic acid. A detailed characterization of the new compounds was performed by IR, NMR and elemental analyses, followed by single-crystal X-ray diffraction experiments for two representatives.

Cytotoxic and Antimicrobial Activity of Dehydrozingerone based Cyclopropyl Derivatives.

A small series of 1-acetyl-2-(4-alkoxy-3-methoxyphenyl)cyclopropanes was prepared, starting from dehydrozingerone (4-(4-hydroxy-3-methoxyphenyl)-3-buten-2-one) and its O-alkyl derivatives. Their microbiological activities toward some strains of bacteria and fungi were tested, as well as their in vitro cytotoxic activity against some cancer cell lines (HeLa, LS174 and A549). All synthesized compounds showed significant antimicrobial activity and expressed cytotoxic activity against tested carcinoma cell lines, but they showed no significant influence on normal cell line (MRC5). Butyl derivative is the most active on HeLa cells (IC50 = 8.63 µm), while benzyl one is active against LS174 and A549 cell lines (IC50 = 10.17 and 12.15 µm, respectively).

Chemistry of spices: bornyl 4-methoxybenzoate from Ferula ovina (Boiss.) Boiss. (Apiaceae) induces hyperalgesia in mice.

UNLABELLED: Ferula ovina (Boiss.) Boiss. is a traditional Iranian flavoring agent used as an ingredient of spices and condiments. METHODS AND RESULTS: GC-MS analyses of F. ovina aerial parts' essential oil revealed the presence of a number of rare aromatic esters of monoterpenic alcohols. The structures of these esters were corroborated by synthesis, and one of them, bornyl 4-methoxybenzoate, turned out to be a new natural compound. The antinociceptive activities of the oil and the new ester were assessed in mice using several different laboratory models. The oil exerted strong peripheral and moderate central analgesic activities. Surprisingly, mice treated with bornyl 4-methoxybenzoate had an increased sensitivity to the noxious stimulus compared to that of the control group. A dynamic hot plate test was used to demonstrate that bornyl 4-methoxybenzoate induces hyperalgesia and not allodynia. CONCLUSION: Essential oil constituents impart this spice with both antinociceptive and hyperalgesic potentially flavor-related properties.