Triazoles in Medicinal Chemistry: Physicochemical Properties, Bioisosterism, and Application

Abstract

Triazole demonstrates distinctive physicochemical properties, characterized by weak basicity, various dipole moments, and significant dual hydrogen bond acceptor and donor capabilities. These features are poised to play a pivotal role in drug−target interactions. The inherent polarity of triazole contributes to its lower logP, suggesting the potential improvement in water solubility. The metabolic stability of triazole adds additional value to drug discovery. Moreover, the metal-binding capacity of the nitrogen atom lone pair electrons of triazole has broad applications in the development of metal chelators and antifungal agents. This Perspective aims to underscore the unique physicochemical attributes of triazole and its application. A comparative analysis involving triazole isomers and other heterocycles provides guiding insights for the subsequent design of triazoles, with the hope of offering valuable considerations for designing other heterocycles in medicinal chemistry. ■ SIGNIFICANCE AND IMPACT• Significance: Triazole rings, including 1,2,3-triazole and 1,2,4-triazole, are pivotal in drug design due to their unique physicochemical properties, serving as versatile alternatives to various aromatic rings and functional groups.• Impact: It emphasizes the influence of the physicochemical properties of triazoles while providing comparative data with other frequently employed pharmacophores in medicinal chemistry. • Innovation: This Perspective discusses the influence of diverse physicochemical properties of triazoles and their strategic application in drug design.

An Update on the Nitrogen Heterocycle Compositions and Properties of U.S. FDA-Approved Pharmaceuticals (2013–2023)

“…The 11th ranked nitrogen heterocycle is 1,2,4-triazole, with nine new small-molecule drugs (Figure ) along with the 1,2,3-triazole drugs daridorexant (approved 1/2022) and suvorexant (approved 8/2014), which are approved for hypotension and insomnia, respectively . This dataset includes the antifungal triazolium drug isavuconazonium (approved 3/2015) and the oxidized triazole HIV/AIDS drug doravirine (approved 8/2018).…”