posted on 2021-04-29, 20:44authored byAshraf
S. Hassan, Gaber O. Moustafa, Hanem M. Awad, Eman S. Nossier, Mohamed F. Mady
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.