Recent Developments in the Synthesis of Tetrazoles and their Pharmacological Relevance

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Abstract

The heterocycle ring tetrazole is an important moiety relevant to medicinal chemistry since it is present in some drugs with clinical importance. Its primary biological activity is being a bioisosteric analogue of the carboxylic acid and cis-amide groups. Its metabolic stability and other physicochemical properties make it an attractive structure for designing and synthesizing new pharmaceuticals. The biological activity of tetrazoles is quite extensive and includes antiviral, antibacterial, anticancer, antifungal, and antioxidant properties; all of them are discussed in this review. The most effective way to obtain tetrazoles is by azide derivatives, either in the starting materials by the cycloaddition [3 + 2] of organic azides and nitriles or by preparing a reactive imidoyl azide intermediate. The nucleophilic behavior of the azide group is discussed when the raw materials include isocyanides. Some other methods include alternative synthetic routes like thermolysis. This review also highlights some of the developments regarding the use of different heterogeneous catalysts to synthesize several tetrazole derivatives.

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Most cited references 89

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Interactions with aromatic rings in chemical and biological recognition.

Emmanuel Meyer, Ronald K. Castellano, François Diederich (2003)

Intermolecular interactions involving aromatic rings are key processes in both chemical and biological recognition. Their understanding is essential for rational drug design and lead optimization in medicinal chemistry. Different approaches-biological studies, molecular recognition studies with artificial receptors, crystallographic database mining, gas-phase studies, and theoretical calculations-are pursued to generate a profound understanding of the structural and energetic parameters of individual recognition modes involving aromatic rings. This review attempts to combine and summarize the knowledge gained from these investigations. The review focuses mainly on examples with biological relevance since one of its aims it to enhance the knowledge of molecular recognition forces that is essential for drug development.

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Tetrazoles via Multicomponent Reactions

Constantinos Neochoritis, Ting Zhao, Alexander Dömling (2019)

Tetrazole derivatives are a prime class of heterocycles, very important to medicinal chemistry and drug design due to not only their bioisosterism to carboxylic acid and amide moieties but also to their metabolic stability and other beneficial physicochemical properties. Although more than 20 FDA-approved drugs contain 1H- or 2H-tetrazole substituents, their exact binding mode, structural biology, 3D conformations, and in general their chemical behavior is not fully understood. Importantly, multicomponent reaction (MCR) chemistry offers convergent access to multiple tetrazole scaffolds providing the three important elements of novelty, diversity, and complexity, yet MCR pathways to tetrazoles are far from completely explored. Here, we review the use of multicomponent reactions for the preparation of substituted tetrazole derivatives. We highlight specific applications and general trends holding therein and discuss synthetic approaches and their value by analyzing scope and limitations, and also enlighten their receptor binding mode. Finally, we estimated the prospects of further research in this field.

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Mechanisms of tetrazole formation by addition of azide to nitriles.

Fahmi Himo, Zachary Demko, Louis Noodleman … (2002)

It is well-known that azide salts can engage nitriles at elevated temperatures to yield tetrazoles; however, there is continued debate as to the mechanism of the reaction. Density functional theory calculations with the hybrid functional B3LYP have been performed to study different mechanisms of tetrazole formation, including concerted cycloaddition and stepwise addition of neutral or anionic azide species. The calculations presented here suggest a previously unsuspected nitrile activation step en route to an imidoyl azide, which then cyclizes to give the tetrazole. The activation barriers are found to correlate strongly with the electron-withdrawing potential of the substituent on the nitrile.