Structural Modifications of Benzimidazoles via Multi‐Step Synthesis and Their Impact on Sirtuin‐Inhibitory Activity

Abstract

Benzimidazole derivatives have been shown to possess sirtuin-inhibitory activity. In the continuous search for potent sirtuin inhibitors, systematic changes on the terminal benzene ring were performed on previously identified benzimidazole-based sirtuin inhibitors, to further investigate their structure-activity relationships. It was demonstrated that the sirtuin activities of these novel compounds followed the trend where meta-substituted compounds possessed markedly weaker potency than ortho- and para-substituted compounds, with the exception of halogenated substituents. Molecular docking studies were carried out to rationalize these observations. Apart from this, the methods used to synthesize the interesting compounds are also discussed.

The Current State of NAD+‐Dependent Histone Deacetylases (Sirtuins) as Novel Therapeutic Targets

“…reported benzimidazoles, such as the benzimidazoles 18 (36) (Fig. ), as a new class of sirtuin inhibitors with a slight selectivity for Sirt2 over Sirt1 . However, the inhibition of other sirtuin isotypes as well as the cellular activity of the benzimidazoles has not been assessed yet.…”

Three‐Component Aminoalkylations Yielding Dihydronaphthoxazine‐Based Sirtuin Inhibitors: Scaffold Modification and Exploration of Space for Polar Side‐Chains

“…In spite of the name histone deacetylases, sirtuins deacylate various other proteins than histones . In the case of SIRT2, important substrates are transcription factors (FOXO1 and FOXO3a ), α‐tubulin , and glucose‐6‐phosphate dehydrogenase (G6PD) .…”

Synthesis of Some Novel 2‐Substitutedbenzyl‐(4)7‐phenyl‐1H‐benzo[d]imidazoles in Mild Conditions as Potent Anti‐Tyrosinase and Antioxidant Agents

“…The reason for this interest, the compounds bearing benzimidazole ring were obtained biologically active molecules. These pharmacological activities are antimicrobial , antiproliferative , antibacterial , receptor antagonists , antitumor activity , cytotoxic activity , antihelmintic resistance , sirtuin inhibitor activity , anti‐MRSA and anti‐VRE agonists , anticancer , antitubercular activity , hepatitis C virus inhibitor , antidiabetic , antihypertensive , and lipase inhibition activity .…”