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

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 1 H -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-((1 H -indol-3-yl)methyleneamino)- N -phenyl-3-(phenylamino)-1 H -pyrazole-4-carboxamide ( 7a ) and 5-((1 H -indol-3-yl)methyleneamino)-3-(phenylamino)- N -(4-methylphenyl)-1 H -pyrazole-4-carboxamide ( 7b ) provided excellent anticancer inhibition performance against the HepG2 cancer cell line with IC 50 values of 6.1 ± 1.9 and 7.9 ± 1.9 μM, respectively, compared to the standard reference drug, doxorubicin (IC 50 = 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.

Synthesis, Characterization, In Vitro Anticancer Potentiality, and Antimicrobial Activities of Novel Peptide–Glycyrrhetinic-Acid-Based Derivatives

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“…Various reports revealed that some kinds of caspases are sponsors for starting intracellular event cascade, while others are effectors, producing their effects further downstream resulting in cellular breakdown by intrinsic protein breakdown. Cell shrinkage, chromatin condensation, and DNA fragmentation are all apoptosis events, which need the involvement of caspase-7and caspase-3 [ 48 , 54 , 56 ]. Accordingly, MCF-7 cells were treated with 5 at its IC 50 concentration of 5 μg/mL for 24 h aiming to detect the change in the level of caspase-3and caspase-7.…”

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Synthesis and biological evaluation of new derivatives of thieno-thiazole and dihydrothiazolo-thiazole scaffolds integrated with a pyrazoline nucleus as anticancer and multi-targeting kinase inhibitors

“…At a density of 1 × 10 6 to 3 × 10 6 cells per dish, MCF-7 cells were seeded in 30 mm tissue culture plates in 5 mL of complete medium. 63 More details in the ESI. †…”

“…The experiment was carried out according to the manufacturer's protocol. 63 More details in the ESI. †…”