Design, one-pot synthesis, computational and biological evaluation of diaryl benzimidazole derivatives as MEK
Teja Ram1, Ankit Kumar Singh1, Prateek Pathak2,3,4
1Department of Pharmaceutical Sciences and Natural Products, Central University of Punjab, Bathinda, Ghudda, India.
Abstract:
MEK mutations are more common in various human malignancies, such as pancreatic cancer (70-90%), mock melanoma (50%), liver cancer (20-40%), colorectal cancer (25-35%), melanoma (15-20%), non-small cell lung cancer (10-20%) and basal breast cancer (1-5%). Considering the significance of MEK mutations in diverse cancer types, the rational design of the proposed compounds relies on the structural resemblance to FDA-approved MEK inhibitors like selumetinib and binimetinib. The compound under design features distinct substitutions at the benzimidazole moiety, specifically at positions 2 and 3, akin to the FDA-approved drugs, albeit differing in positions 5 and 6. Subsequent structural refinement was guided by key elements including the DFG motif, hydrophobic pocket and catalytic loop of the MEK protein. A set of 15 diverse diaryl benzimidazole derivatives (S1-S15) were synthesized via a one-pot approach and characterized through spectroscopic techniques, including MASS, IR, 1H NMR and 13C NMR. In vitro anticancer activities of all the synthesized compounds were evaluated against four cancer cell lines, A375, HT -29, A431 and HFF, along with the standard drug trametinib. Molecular docking was performed for all synthesized compounds (S1-15), followed by 950 ns molecular dynamics simulation studies for the promising compounds S1, S5 and S15. The stability of these complexes was assessed by calculating the root-mean-square deviation, solvent accessible surface area and gyration radius relative to their parent structures. Additionally, free energy of binding calculations were performed. Based on the biological and computational results, S15 was the most potent compound and S1 and S5 are comparable to the standard drug trametinib.Communicated by Ramaswamy H. Sarma.
Insights
New MEK inhibitors targeting cancer were designed and synthesized. Compound S15 showed potent anticancer activity, while S1 and S5 demonstrated efficacy comparable to trametinib.
Area of Science:
- Medicinal Chemistry
- Molecular Biology
- Computational Chemistry
Background:
- MEK mutations are prevalent in numerous cancers, including pancreatic, liver, and colorectal cancers, highlighting MEK as a critical therapeutic target.
- Existing MEK inhibitors like selumetinib and binimetinib provide a structural basis for designing novel anticancer agents.
Purpose of the Study:
- To design and synthesize novel diaryl benzimidazole derivatives as potential MEK inhibitors.
- To evaluate the in vitro anticancer activity and computational binding stability of the synthesized compounds.
Main Methods:
- Synthesis of 15 diaryl benzimidazole derivatives (S1-S15) via a one-pot approach.
- Characterization using spectroscopic techniques (MASS, IR, 1H NMR, 13C NMR).
- In vitro anticancer activity screening against A375, HT-29, A431, and HFF cell lines, with molecular docking and molecular dynamics simulations for promising compounds.
Main Results:
- All 15 compounds were synthesized and characterized.
- Compound S15 exhibited the most potent in vitro anticancer activity.
- Compounds S1 and S5 showed comparable efficacy to the standard drug trametinib.
- Molecular dynamics simulations confirmed the stability of complexes formed by S1, S5, and S15.
Conclusions:
- Diaryl benzimidazole derivatives represent a promising class of MEK inhibitors.
- Compound S15 is identified as a lead candidate for further anticancer drug development.
- Compounds S1 and S5 warrant further investigation due to their comparable efficacy to trametinib.
