Privileged Scaffolds or Promiscuous Binders: A Glance of Pyrrolo[2,1-f][1,2,4]triazines and Related Bridgehead Nitrogen Heterocycles in Medicinal Chemistry

Yu'ning      Song; Peng      Zhan; Qingzhu      Zhang; Xinyong      Liu

doi:10.2174/1381612811319080020

Abstract

Pyrrolo[2,1-f][1,2,4]triazine template, a unique bridgehead nitrogen heterocycle, certainly deserves the title of "privileged scaffold" in the drug discovery field because of the versatility and potential to yield derivatives with a wide range of biological activities, such as anti-anaplastic lymphoma kinase (ALK), Janus kinase 2 (JAK2), VEGFR-2, EGFR and/or HER2, Met kinase, p38α mitogenactivated protein (MAP) kinase and insulin-like growth factor receptor (IGF-1R) kinase activities, etc. These different biological properties of pyrrolo[2,1-f][1,2,4]triazine derivatives have motivated new studies in searching for novel derivatives with improved activity and also other applications in pharmaceutical field. However, no systematic review is available in the literature on the pyrrolo[2,1- f][1,2,4]triazine derivatives concerning the design of potent drug-like compounds. Owing to the importance of this heterocyclic system, the present paper is an attempt to the pharmacological activities, structural modifications and the structure-activity relationship (SAR) reported for bridgehead nitrogen heterocycles in the current literature, making an effort to highlight the importance and therapeutic potentials of the pyrrolo[2,1-f][1,2,4]triazine scaffold and its bridgehead nitrogen bioisosters as heterocyclic privileged medicinal scaffolds.

Keywords: Heterocycle, Bridgehead nitrogen heterocycle, Privileged scaffold, Bioisosters, Pyrrolo[2, 1-f][1, 2, 4]triazine, Biological activities, Drug design, anti-anaplastic lymphoma kinase (ALK), Janus kinase 2 (JAK2), VEGFR-2