One-Pot Parallel Synthesis of 5-(Dialkylamino)tetrazoles

Abstract

Two protocols for the combinatorial synthesis of 5-(dialkylamino)tetrazoles were developed. The best success rate (67%) was shown by the method that used primary and secondary amines, 2,2,2-trifluoroethylthiocarbamate, and sodium azide as the starting reagents. The key steps included the formation of unsymmetrical thiourea, subsequent alkylation with 1,3-propane sultone and cyclization with azide anion. A 559-member aminotetrazole library was synthesized by this approach; the overall readily accessible (REAL) chemical space covered by the method exceeded 7 million feasible compounds.

The iterative application of a large chemical space in the drug discovery process

“…Over the last two years, we proposed two approaches to deliver multimillion chemical libraries based on heterocyclic scaffold-like cores [8,14]. The chemical space generated based on the approaches meets the REAL paradigm:…”

“…All top-scoring molecules were selected for the synthesis. The synthesis performed as descri-bed [8,14] resulted in 29 compounds (72.5 % success rate). The list of the compounds obtained with docking scores is given in the Supporting Information File.…”

“…The chemical space was generated from the instock available building blocks using reactions of the formation of aminotetrazoles and aminotriazoles [8,14]. The whole chemical space comprised 674 million unique compounds.…”

“…Many approaches exist to utilize fewer resources by sampling a chemical space before the screen [13]. In this work, we study a part of the REAL space built utilizing two transformations [8,14] applying sampling to the output to get a representative small dockable set of compounds. We further demonstrate the advantages of having virtual libraries of synthesizable compounds in the primary hit identification showing the speed and efficacy of such an approach to support fast turnaround.…”

Novel hybrid isoindole‐1,3(2H)‐dione compounds containing a 1H‐tetrazole moiety: Synthesis, biological evaluation, and molecular docking studies

“…[10] These compounds have attracted interest due to their unparalleled structure and various biological activities, such as anti-inflammatory, antimycobacterial, antiviral, antifungal, antitumor, anticonvulsant, and antihypertensive. [11][12][13][14][15][16] Therefore, these compounds are widely used in many fields, such as chemistry, medicine (Figure 2), [17] the paint and photography industries, and agriculture. [18] Tetrazole chemistry has continued to develop intensively in all directions in recent years.…”