Synthesis of new arylazopyrazoles as apoptosis inducers: Candidates to inhibit proliferation of MCF‐7 cells

Abstract

New 4‐arylazo‐3,5‐diamino‐1H‐pyrazole derivatives substituted in the 4‐aryl ring with the acetyl moiety were designed and synthesized. The antiproliferative activity of the novel arylazopyrazoles was examined against the MCF‐7 cell line. Among all target compounds, 8b (IC50 3.0 µM) and 8f (IC50 4.0 µM) displayed higher cytotoxicity as compared with the reference standard imatinib (IC50 7.0 µM). Further studies to explore the mechanism of action were performed on the most active hit of our library, 8b, via anti‐CDK2 kinase activity. It demonstrated good inhibitory effects for CDK2 (IC50 0.24 µM) with 62.5% inhibition, compared with imatinib. The cell cycle analysis in the MCF‐7 cell line revealed apoptosis induction by 8b and cell cycle arrest at the S phase. Docking in the CDK2 active site and pharmacophore modeling confirmed the affinity of 8b to the CDK2 active site. Absorption, distribution, metabolism, and excretion studies revealed that our target compounds are orally bioavailable, with no permeation through the blood–brain barrier.

Amino-Pyrazoles in Medicinal Chemistry: A Review

“…The cytotoxic properties were evaluated in vitro against human breast cancer cells (MCF-7) and compound 41 (Figure 14) was seen to be the most active (IC 50 of 26.86 mM). In vitro, a kinase assay individuated CDK2/cyclin E as a potential target of the newly synthesised derivatives [93].…”

“…The cytotoxic properties were evaluated in vitro against human breast cancer cells (MCF-7) and compound 41 (Figure14) was seen to be the most active (IC50 of 26.86 mM). In vitro, a kinase assay individuated CDK2/cyclin E as a potential target of the newly synthesised derivatives[93].Furthermore, a library of 3,5-diamino-N-aryl-1H-pyrazole-4-carbothioamides was identified as a potential class of HIV-1 inhibitors endowed with innovative mechanisms of action. The aim of the project was to synthesise new chemical entities able to inhibit different viral functions to provide a significant advantage against drug-resistant variants.…”

A comprehensive analysis of the role of molecular docking in the development of anticancer agents against the cell cycle CDK enzyme

“…They displayed the binding energies of −8.90 and −8.60 kcal/mol for 58 and 59, respectively (Ghosh et al, 2021). Ismail et al (2021) synthesized new arylazo-pyrazoles derivatives and used the MTT technique to examine their antiproliferative activity. They observed that two compounds with IC 50 of 3.0 and 4.0 µM displayed higher cytotoxicity compared with the reference standard Imatinib (IC 50 of 7.0 µM).…”

“…The acetophenone moiety formed more hydrophobic interactions with the amino acids Asp145 and Leu134. After docking studies, they performed ADME analysis by SwissADME, Molsoft, Pre-ADME websites, and DataWarrior software, which also revealed that compound 60 is orally bioavailable (Ismail et al, 2021). 55) and pyrazole-indole hybrids (56, 57) displaying potent CDK2 inhibition.…”

Novel quinoxaline-3-propanamides as VGFR-2 inhibitors and apoptosis inducers

“…Fig. 1) and as a continuation of our prior work in the eld of the design and synthesis of new anticancer medicines, [19][20][21][22][23][24][25][26] a new series of 6-chloroquinoxaline-3propanamides have been designed as sunitinib's mimetic to optimize pharmacodynamics properties and to overcome certain pharmacokinetic problems demonstrated on sunitinib clinical use such as, BBB permeation and being P-gp substrate.…”