Solid-Phase Synthesis of Arylpiperazine Derivatives and Implementation of the Distributed Drug Discovery (D3) Project in the Search for CNS Agents

Abstract

We have successfully implemented the concept of Distributed Drug Discovery (D3) in the search for CNS agents. Herein, we demonstrate, for the first time, student engagement from different sites around the globe in the development of new biologically active compounds. As an outcome we have synthesized a 24-membered library of arylpiperazine derivatives targeted to 5-HT1A and 5-HT2A receptors. The synthesis was simultaneously performed on BAL-MBHA-PS resin in Poland and the United States, and on BAL-PS-SynPhase Lanterns in France. The D3 project strategy opens the possibility of obtaining potent 5-HT1A/5-HT2A agents in a distributed fashion. While the biological testing is still centralized, this combination of distributed synthesis with screening will enable a D3 network of students world-wide to participate, as part of their education, in the synthesis and testing of this class of biologically active compounds.

A New and Efficient Method for the Synthesis of 3,4-Disubstituted Pyrrolidine-2,5-diones

“…Owing to their wide range of biological activities and pharmacological properties [1,2,3,4,5,6,7,8,9,10,11,12,13] the synthesis of substituted pyrrolidine-2,5-diones has become a field of increasing interest in organic synthesis during the last few decades. The approach based on nucleophilic acyl substitution involving 1,4-dicarboxylic acids [3,4,5,6,14] or their derivatives such as succinic anhydrides [7,8,9,14,15,16,9,14] with nucleophiles, e.g., amines or amides, is one of the most used methods for preparing pyrrolidine-2,5-diones.…”

“…The approach based on nucleophilic acyl substitution involving 1,4-dicarboxylic acids [3,4,5,6,14] or their derivatives such as succinic anhydrides [7,8,9,14,15,16,9,14] with nucleophiles, e.g., amines or amides, is one of the most used methods for preparing pyrrolidine-2,5-diones. Other commonly used derivatives of 1,4-dicarboxylic acids are the amides [11,12,13,17,18,19,13,17], in these cases the nucleophilic acyl substitution is an intramolecular process. Some rearrangements which yield pyrrolidine-2,5-diones are also reported [20,21,22,23].…”