1,3‐Diazepine: A privileged scaffold in medicinal chemistry

Abstract

Privileged structures have been widely used as effective templates for drug discovery. While benzo‐1,4‐diazepine constitutes the first historical example of such a structure, the 1,3 analogue is just as rich in terms of applications in medicinal chemistry. The 1,3‐diazepine moiety is present in numerous biological active compounds including natural products, and is used to design compounds displaying a large range of biological activities. It is present in the clinically used anticancer compound pentostatin, in several recent FDA approved β‐lactamase inhibitors (e.g., avibactam) and also in coformycin, a natural product known as a ring‐expanded purine analogue displaying antiviral and anticancer activities. Several other 1,3‐diazepine containing compounds have entered into clinical trials. This heterocyclic structure has been and is still widely used in medicinal chemistry to design enzyme inhibitors, GPCR ligands, and so forth. This review endeavours to highlight the main use of the 1,3‐diazepine scaffold and its derivatives, and their applications in medicinal chemistry, drug design, and therapy. We will focus more particularly on the development of enzyme inhibitors incorporating this scaffold, with a strong emphasis on the molecular interactions involved in the inhibition mechanism.

1,3‐Diazepine Derivatives: Strategies for Synthesis

“…of titanium isopropoxide at room temperature for 4 h Scheme 7. Synthesis of dibenzo [1,3]diazepine 26. [16] Scheme 8.…”

“…of tosyl isocyanate in dry acetonitrile at room temperature. Imidazo [4,5-d] [1,3] diazepine derivatives 111 a-d were obtained in high yields (88 % to 96 %).…”

“…In 1996, Dias et al reported the synthesis of imidazo[4,5d] [1,3]diazepine derivatives from an unexpected cyclization. [43] Initially 6-cyano-2-oxopurine derivatives 110 were expected (Scheme 28), thanks to a 6-exo-trig ring closure of the intermediary 109.…”

“…In 2003, Araki et al reported the formation of 5-ethoxycarbonyl-7-hexyl-2,4-diphenyl-6H- [1,3]diazepine 126 as a side product during the reaction of condensation between a cyclopropene and a two-fold excess of nitrile to prepare pyrrole derivatives. [47] The most probable reaction way to explain the diazepine formation is illustrated in Scheme 32.…”

“…The 1,3‐diazepine scaffold is considered as a privileged structure in drug discovery [1] . It is found in both natural and synthetic compounds and displays a large variety of biological activities, e. g .…”