Design, Synthesis, Anticancer Evaluation, Enzymatic Assays, and a Molecular Modeling Study of Novel Pyrazole-Indole Hybrids.

Ashraf S Hassan,Mohamed F Mady,Gaber O Moustafa,Eman S Nossier,Hanem M Awad

doi:10.1021/acsomega.1c01604

Ashraf S Hassan, Mohamed F Mady + Show 3 more

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https://doi.org/10.1021/acsomega.1c01604

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Abstract

The molecular hybridization concept has recently emerged as a powerful approach in drug discovery. A series of novel indole derivatives linked to the pyrazole moiety were designed and developed via a molecular hybridization protocol as antitumor agents. The target compounds (5a–j and 7a–e) were prepared by the reaction of 5-aminopyrazoles (1a–e) with N-substituted isatin (4a,b) and 1H-indole-3-carbaldehyde (6), respectively. All products were characterized via several analytical and spectroscopic techniques. Compounds (5a–j and 7a–e) were screened for their cytotoxicity activities in vitro against four human cancer types [human colorectal carcinoma (HCT-116), human breast adenocarcinoma (MCF-7), human liver carcinoma (HepG2), and human lung carcinoma (A549)] using the MTT assay. The obtained results showed that the newly synthesized compounds displayed good-to-excellent antitumor activity. For example, 5-((1H-indol-3-yl)methyleneamino)-N-phenyl-3-(phenylamino)-1H-pyrazole-4-carboxamide (7a) and 5-((1H-indol-3-yl)methyleneamino)-3-(phenylamino)-N-(4-methylphenyl)-1H-pyrazole-4-carboxamide (7b) provided excellent anticancer inhibition performance against the HepG2 cancer cell line with IC50 values of 6.1 ± 1.9 and 7.9 ± 1.9 μM, respectively, compared to the standard reference drug, doxorubicin (IC50 = 24.7 ± 3.2 μM). The two powerful anticancer compounds (7a and 7b) were further subjected to cell cycle analysis and apoptosis investigation in HepG2 using flow cytometry. We have also studied the enzymatic assay of these two compounds against some enzymes, namely, caspase-3, Bcl-2, Bax, and CDK-2. Interestingly, the molecular docking study revealed that compounds 7a and 7b could well embed in the active pocket of the CDK-2 enzyme via different interactions. Overall, the prepared pyrazole–indole hybrids (7a and 7b) can be proposed as strong anticancer candidate drugs against various cancer cell lines.

Highlights

Cancer is one of the significant health problems and the second reason for deaths globally
The molecular docking study revealed that compounds 7a and 7b could well embed in the active pocket of the cyclin-dependent kinases (CDKs)-2 enzyme via different interactions
It was found that most human cancers are associated with the deregulation of cyclin-dependent kinases (CDKs)

Summary

Introduction

Cancer is one of the significant health problems and the second reason for deaths globally. It is well known that protein kinases play a vital role in regulating cell function. These proteins can be used as a molecular target for designing new cancer inhibitors. CDKs are a family of serine-threonine kinases that regulate cell cycle progression via the phosphorylation process. CDK-2 is an S/T-protein kinase required for the cell cycle G1/S transition. The inhibition of CDK-2 modulates siRNA and generates cell cycle arrest and apoptosis, leading to decreased proliferation of several cancer cells. This class of enzymes has attracted great attention for the designing and preparation of selective cancer inhibitors. There is a clear need to design and synthesize novel, selective, and less-toxic bioactive antitumor agents.[2−4]

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