Visible Light-Promoted Green and Sustainable Approach for One-Pot Synthesis of 4,4'-(Arylmethylene)bis(1H-pyrazol-5-ols), In Vitro Anticancer Activity, and Molecular Docking with Covid-19 Mpro

Abstract

A visible light-promoted, efficient, green, and sustainable strategy has been adopted to unlatch a new pathway toward the synthesis of a library of medicinally important 4,4'-(arylmethylene)bis(1H-pyrazol-5-ols) moieties using substituted aromatic aldehydes and sterically hindered 3-methyl-1-phenyl-2-pyrazoline-5-one in excellent yield. This reaction shows high functional group tolerance and provides a cost-effective and catalyst-free protocol for the quick synthesis of biologically active compounds from readily available substrates. Synthesized compounds were characterized by spectroscopic techniques such as IR, ¹HNMR, ¹³CNMR, and single-crystal XRD analysis. All the synthesized compounds were evaluated for their antiproliferative activities against a panel of five different human cancer cell lines and compared with Tamoxifen using MTT assay. Compound 3m exhibited maximum antiproliferative activity and was found to be more active as compared to Tamoxifen against both the MCF-7 and MDA-MB-231 cell lines with an IC₅₀ of 5.45 and 9.47 μM, respectively. A molecular docking study with respect to COVID-19 main protease (M^pro) (PDB ID: 6LU7) has also been carried out which shows comparatively high binding affinity of compounds 3f and 3g (-8.3 and -8.8 Kcal/mole, respectively) than few reported drugs such as ritonavir, remdesivir, ribacvirin, favipiravir, hydroxychloroquine, chloroquine, and olsaltamivir. Hence, it reveals the possibility of these compounds to be used as effective COVID-19 inhibitors.

Figure 1

Few examples of biologically active pyrazolones.

Scheme 1. Optimization of Reaction Conditions for the Synthesis of 4,4́-(Arylmethylene)bs(1H-pyrazo-5-ol) From Different Aldehyde Derivatives and 3-Methyl-1-Phenyl-2-Pyrazoline-5-One

Scheme 2. Substrate Scope of 4,4́-(Arylmethylene)bis(1H-pyrazol-5-ol) Under the Optimized Reaction Condition

Figure 2

Ortep diagram of compound 3f with CCDC 2178033.

Figure 3

Cytotoxicity assay of some active 4,4′-(arylmethylene)bis(1H-pyrazol-5-ol) derivatives in MCF-7 cells. Cell lines were treated with (0, 1, 5, 10, 15, and 20 μM) for 48 h, after which the cell viability was measured by MTT assay; results are expressed as mean ± SEM; N = 4, at all concentrations of TAM, 3j–3m, p values are p < 0.05 but p > 005 control vs 1 μM TAM, for 3j, 10 μM vs. 15 μM.

Figure 4

Cytotoxicity assay of some active 4,4’′-(arylmethylene)bis(1H-pyrazol-5-ol) derivatives in MDA-MB-231 cells. Cell lines were treated with (0, 1, 5, 10, 15, and 20 μM) for 48  h, after which the cell viability was measured by MTT assay; results are expressed as mean ± SEM; N = 4, p values are p < 0.05.

Figure 5

Graphical representation of calculated IC₅₀ values for the selected active compounds (3j, 3l, and 3m) and TAM, against a panel of five cancerous and normal cell lines. Compounds showed an IC₅₀ value of more than 40 μM HEK-293cell lines; hence, to plot a graph of the IC₅₀ value against the selected compounds, we considered the value of 40 μM as IC₅₀. In the case of the standard drug (TAM), the experiment was not performed against Hela PC- 3, Ishikawa cell lines, and HEK-293 cells.

Figure 6

Structural activity relationship of bis-pyrazole derivatives against MCF-7 cell lines.

Figure 7

3D molecular docking models showing interaction of synthesized ligands with COVID-19 (M^pro) (PDB ID: 6LU7).

Figure 8

2D representation of different interacting modes of synthesized ligands with COVID-19 (M^pro) (PDB ID: 6LU7).

Figure 8

2D representation of different interacting modes of synthesized ligands with COVID-19 (M^pro) (PDB ID: 6LU7).

Scheme 3. Plausible Mechanistic Pathway for Synthesis of 4,4′-(Arylmethylene)bis(1H-pyrazol-5-ol)