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image of Discovery of 5-(Substituted Phenyl)-2-aryl Benzimidazole Derivatives as SIRT1 Activators: Their Design, in silico Studies, Synthesis, and in vitro Evaluation

Abstract

Aim

Silent information regulator two homologue one (SIRT1) is an emerging target for managing metabolic disorders. This study aimed to synthesize novel 5-(substituted phenyl)-2-aryl benzimidazole derivatives and evaluate them for SIRT1 activation.

Methods

The compounds were designed according to the findings of the QSAR models framed in our previous studies. Molecular docking and dynamics studies were also performed to explore the interactions of designed compounds with the active site of the SIRT1 enzyme using AutoDock Vina and Schrödinger Maestro version 11.8.012, respectively. Compounds with good binding affinity were synthesized by Suzuki-Miyaura cross-coupling and spectrally characterized. The molecules were evaluated for their SIRT1 activation properties using a fluorescent screening kit. Based on the results of a structure-activity relationship was established. SwissADME was employed to calculate the pharmacokinetics characteristics of the synthesized molecules.

Results

The molecular docking studies revealed that all the activators were effectively docked in the catalytic active site. All compounds demonstrated interactions with important amino acids like Glu230 and Arg446. In molecular dynamics simulations, the root mean square deviation (RMSD) of compound and protein SIRT1 remained stable, , below 3mm. Compound , 4-(2-(3,4-dihydroxy-5-nitrophenyl)--benzoimidazol-5-yl)benzaldehyde, was the most potent compound with an EC value of 0.006 mM (±0.001) and maximum activation of 240.5%. All the synthesized compounds had acceptable theoretical ADME profiles, and drug-likeness properties complied with Lipinski’s rule.

Conclusion

According to the findings, synthesized compounds may be viable leads for SIRT1 activators and may be used to advance preclinical research utilizing animal models.

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2024-10-10
2024-11-26

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Discovery of 5-(Substituted Phenyl)-2-aryl Benzimidazole Derivatives as SIRT1 Activators: Their Design, in silico Studies, Synthesis, and in vitro Evaluation
Bentham Science Publishers ; https://doi.org/10.2174/0109298673330534240924104941
/content/journals/cmc/10.2174/0109298673330534240924104941
/content/journals/cmc/10.2174/0109298673330534240924104941
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  • Article Type:     Research Article
Keywords: SIRT1 activators ; molecular dynamics ; benzimidazole ; ADME ; molecular docking ; suzuki-miyaura cross-coupling ; metabolic disorder

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