Design, Synthesis, and Molecular Docking Study of New Indole Derivatives as BRD4 Inhibitors

Abstract

Bromodomain-containing protein 4, an epigenetic reader, was considered as a promising drug target for human diseases, such as cancers and cardiac remodeling. This protein contains a pair of bromodomains (BD1 and BD2). Selective inhibition of bromodomains is critical for maintaining cell homeostasis. In the present work we made use of the molecular hybridization strategy to design and synthesize a novel series of indole derivatives, specifically (3-[5-(methylsulfanyl)-4-m-tolyl-4H-1,2,4-triazol-3-yl]-1H-indole, 5-(1H-indol-3-yl)-4-p-tolyl-4H-1,2,4-triazole-3-thiol; 5-(1H-indol-3-yl)-4-(o-tolyl)-4H-1,2,4-triazole-3-thiol, and 4-(3-chlorophenyl)-5-(1H-indol-3-yl)-4H-1,2,4-triazole-3-thiol), as well as 3-[5-(methylsulfanyl)-4-m-tolyl-4H-1,2,4-triazol-3-yl]-1H-indole as potential BRD4 inhibitors. 3-[5-(Methylsulfanyl)-4-(m-tolyl)-4H-1,2,4-triazol-3-yl]-1H-indole showed the highest inhibitory activity against BRD4 BD2 with an inhibition rate of 62% at 20 μM. In addition, this compound was found to work as a selective BD2 inhibitor: its inhibitory effect on BD2 is 8 times stronger than on BD1. The molecular docking study revealed critical interactions between 5-(methylsulfanyl)-4-(m-tolyl)-4H-1,2,4-triazol-3-yl]-1H-indole and Asn433, His437, and Pro375 and predicted good drug likeness for this derivative, which makes it a promising candidate for use as a lead compound for further drug design and development.