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 1 H- or 2 H-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.

Tetrazoles via Multicomponent Reactions.

Properties of responsible for biological activity tetrazoles are considered. Examples are given of active pharmaceutical ingredients of modern drugs containing the tetrazole ring in the molecular structure. New publications on the synthesis and investigations of biological activity of promising tetrazole-containing compounds are cited.

Medicinal chemistry of tetrazoles

This short review compiles the main results of the studies in tetrazole chemistry published in the period 2009–2016. Attention is directed to the structure, reactivity, synthetic problems, functionalization, and also to the application of derivatives of this class of polynitrogen heterocyclic compounds. New conditions are revealed of the tetrazole synthesis underpinned by the use of versatile catalytic systems, ionic liquids, superacids, microwave activation, microreactor techniques, etc. Main trends in the development of the tetrazole chemistry that are helping to focus the efforts of researchers on novel, important, and promising directions of study are considered.

Developments in Tetrazole Chemistry (2009–16)

A series of new tetrazole derivatives are synthesized from Baylis–Hillman allyl amines in a clean, efficient and straightforward manner. The stereochemistry of the double bond is confirmed by X-ray diffraction data. These compounds are evaluated for in vitro anticancer activity against five cancer cell lines. Most of the compounds exhibited good anticancer activity in micro molar concentration out of 16 compounds synthesized and screened. Furthermore, the compound 5o has good binding affinity to calf thymus DNA (ct DNA), as assayed by UV-vis absorption and fluorescence spectroscopic methods.

Synthesis and biological evaluation of tetrazole containing compounds as possible anticancer agents

Amantadine inhibits the M2 proton channel of influenza A virus, yet its clinical use has been limited by the rapid emergence of amantadine-resistant virus strains. We have synthesized and characterized a series of polycyclic compounds designed as ring-contracted or ring-expanded analogues of amantadine. Inhibition of the wild-type (wt) M2 channel and the A/M2-S31N and A/M2-V27A mutant ion channels were measured in Xenopus oocytes using two-electrode voltage clamp (TEV) assays. Several bisnoradamantane and noradamantane derivatives inhibited the wt ion channel. The compounds bind to a primary site delineated by Val27, Ala30, and Ser31, though ring expansion restricts the positioning in the binding site. Only the smallest analogue 8 was found to inhibit the S31N mutant ion channel. The structure−activity relationship obtained by TEV assay was confirmed by plaque reduction assays with A/H3N2 influenza virus carrying wt M2 protein.

Alexey S. Gavrilov

Papers

Synthesis and anti-viral activity of azolo-adamantanes against influenza A virus.

Extraction of Nickel from Oxidized Nickel Ores by Heap Leaching