Novel benzofurane-pyrazole derivatives with anti-inflammatory, cyclooxygenase inhibitory and cytotoxicity evaluation

Novel benzofurane-pyrazolone hybrids have been synthesized for evaluating their anti-inflammatory and cytotoxic properties. 4-(2-chloroacetyl)-1,5-dimethyl-2-phenyl-1,2-dihydro-3H-pyrazol-3-one were reacted with α-hydroxy aldehyde or α-hydroxy ketone derivatives to obtain nine novel pyrazolone derivatives. Structures were successfully elucidated by 1H NMR, 13C NMR, IR and HRMS. Enzyme inhibitory activity was measured on cyclooxygenases (COXs) as considered to address anti-inflammatory activity. Compound 2 showed the highest activity on both COX-1 and COX-2 subtypes with 12.0 μM and 8.0 μM IC50, respectively. This activity was found close to indomethacin COX-2 inhibition measured as 7.4 μM IC50. Rest of the compounds (1, 3–9) showed 10.4–28.1 μM IC50 on COX-2 and 17.0–35.6 μM IC50 on COX-1 (Compound 1 has no activity on COX-1). Tested compounds (1–9) showed activity on NO production. Only compound was the 4, which showed a low inhibition on IL-6 levels. Cell viability was up to 60% at 100 μM for all compounds (1–9) on RAW 264.7 and NIH3T3 cell lines, thus compounds were reported to be noncytotoxic.

Structural Requirements of 1-(2-Pyridinyl)-5-pyrazolones for Disproportionation of Boronic Acids

We observed an unusual formation of four-coordinate boron(III) complexes from the reaction of 1-(2-pyridinyl)-5-pyrazolone derivatives with arylboronic acids in the basic media. The exact mechanism is not clear; however, the use of unprotected boronic acid and the presence of a bidentate ligand appeared to be the key structural requirements for the transformation. The results suggest that base-promoted disproportionation of arylboronic acid with the assistance of the [N,O]-bidentate ligation of 1-(2-pyridinyl)-5-pyrazolone should take place and facilitate the formation of pyrazole diarylborinate. Experiments to obtain a deeper understanding of its mechanism are currently underway.

Computer-aided approaches reveal trihydroxychroman and pyrazolone derivatives as potential inhibitors of SARS-CoV-2 virus main protease

COVID-19 was declared a pandemic by the World Health Organization (WHO) in March 2020. The disease is caused by severe acute respiratory syndrome coronavirus 2 (SARSCoV-2). The aim of this study is to target the SARS-CoV-2 virus main protease (Mpro) via structure-based virtual screening. Consequently, > 580,000 ligands were processed via several filtration and docking steps, then the top 21 compounds were analysed extensively via MM-GBSA scoring and molecular dynamic simulations. Interestingly, the top compounds showed favorable binding energies and binding patterns to the protease enzyme, forming interactions with several key residues. Trihydroxychroman and pyrazolone derivatives, SN02 and SN18 ligands, exhibited very promising binding modes along with the best MM-GBSA scoring of –40.9 and –41.2 kcal mol−1, resp. MD simulations of 300 ns for the ligand-protein complexes of SN02 and SN18 affirmed the previously attained results of the potential inhibition activity of these two ligands. These potential inhibitors can be the starting point for further studies to pave way for the discovery of new antiviral drugs for SARS-CoV-2.

Performance of PLS, GA-PLS and OSC-GA-PLS Models in QSAR Study of Pyrazolone Derivatives Inhibitory Activity, and Image Processing for New Compounds Designing

Nowadays, Pyrazolone and its derivatives have gained a lot of attention due to their biological and medicinal applications. These compounds have antimicrobial, antifungal and anticancer properties. Therefore, using simple methods to prepare these compounds is important. Pyrazolone is one of the inhibitors of kinase domain containing receptor KDR or VEGFR-2. In this study, Quantitative Structure-Activity Relationship (QSAR) analysis was used to predict the inhibitory activity of new pyrazolone derivatives. Also, Bi-dimensional images were used to calculate pixels for QSAR modeling. Furthermore, the partial least squares (PLS) was used to establish a relationship between IC50-dependent variables and independent variables, i.e., pixels or hidden variables. In addition, Genetic Algorithm (GA) was used in PLS method (GA-PLS) to select the descriptors. In this method, the variables which selected to form the calibration model had negligible errors with acceptable characteristics. Pre-processing methods such as Orthogonal Signal Correction (OSC) were used to provide a suitable input for modeling as well as to improve the results of the GA (OSC-GA-PLS). Furthermore, Root Mean Squared Error of Prediction (RMSEP) was used to assess the performance of the models to predict the pIC50 of the studied compounds, the value of which was obtained equal to 0.30, 0.22, and 0.19 for PLS, GA-PLS and OSC-GA-PLS models, respectively. Finally, the proposed QSAR model was developed with the OSC-GA-PLS method to predict the inhibitory activity of the new compounds.

Stretchable chiral pockets for palladium-catalyzed highly chemo- and enantioselective allenylation

Pyrazolones are a vital class of heterocycles possessing various biological properties and much attention is paid to the diversified synthesis of enantiopure pyrazolone derivatives. We describe here the development of diphenylphosphinoalkanoic acid based chiral bisphosphine ligands, which are successfully applied to the palladium-catalyzed asymmetric allenylation of racemic pyrazol-5-ones. The reaction affords C-allenylation products, optically active pyrazol-5-ones bearing an allene unit, in high chemo- and enantioselectivity, with DACH-ZYC-Phos-C1 as the best ligand. The synthetic potential of the C-allenylation products is demonstrated. Furthermore, the enantioselectivity observed with DACH-ZYC-Phos-C1 is rationalized by density functional theory studies.