Targeting AKT2 in MDA-MB-231 Cells by Pyrazole Hybrids: Structural, Biological and Molecular Docking Studies

Area of Science:

• Medicinal Chemistry
• Organic Synthesis
• Pharmacology

Background:

• Triple-negative breast cancer (TNBC) remains a challenging malignancy with limited targeted therapies.
• Pyrazolic compounds have shown diverse biological activities, necessitating further exploration for novel therapeutic agents.
• Developing multi-drug candidates with broad-spectrum activity is crucial for combating drug resistance.

Purpose of the Study:

• To synthesize novel pyrazolic hybrids incorporating naphthalene, p-chlorobenzene, o-phenol, and toluene moieties.
• To evaluate the cytotoxic activity of these synthesized compounds against MDA-MB-231 (TNBC) cells.
• To investigate the potential of these compounds as Akt2 inhibitors and assess their drug-likeness and antitubercular activity.

Main Methods:

• Claisen Schmidt condensation reaction was employed for the synthesis of pyrazolic hybrids.
• Spectroscopic techniques (e.g., NMR, Mass Spectrometry) were used for characterization.
• In vitro cytotoxic assays (IC50 determination), in silico molecular docking against Akt2, ADME prediction, and antitubercular activity screening were performed.

Main Results:

• Two compounds, 4b and 5a, exhibited potent cytotoxic activity against MDA-MB-231 cells with IC50 values of 47.72 μM and 24.25 μM, respectively.
• Morphological changes in cancer cells indicated apoptosis induction.
• In silico studies suggested potential inhibition of Akt2 by specific pyrazolic hybrids and favorable pharmacokinetic properties for sub-lingual absorption.
• Promising antitubercular activity was observed for these compounds.

Conclusions:

• The synthesized pyrazolic hybrids demonstrate significant potential as cytotoxic agents against TNBC and as antitubercular agents.
• Compounds with substitutions at less sterically hindered positions showed enhanced activity.
• These pyrazolic hybrids represent promising multi-drug candidates warranting further investigation.