Heterocycle-Based Multicomponent Reactions in Drug Discovery: From Hit Finding to Rational Design

Abstract

In the context of the structural complexity necessary for a molecule to selectively display a therapeutical action and the requirements for suitable pharmacokinetics, a robust synthetic approach is essential. Typically, thousands of relatively similar compounds should be prepared along the drug discovery process. In this respect, heterocycle-based multicomponent reactions offer advantages over traditional stepwise sequences in terms of synthetic economy, as well as the fast access to chemsets to study the structure activity relationships, the fine tuning of properties, and the preparation of larger amounts for preclinical phases. In this account, we briefly summarize the scientific methodology backing the research line followed by the group. We comment on the main results, clustered according to the targets and, finally, in the conclusion section, we offer a general appraisal of the situation and some perspectives regarding future directions in academic and private research.

Six‐Component Reactions and Beyond: The Nuts and Bolts

“…However, following such discovery the mechanistic hindsight one gains illuminates discussion and provides avenues for subsequent rational reaction design via MCR strategies [54,55] . Despite the undeniable role of serendipity in MCR development, such observations significantly wane in attempts to afford high‐order MCRs where rational design plays a significantly more important role [56] . Thus, with the advent of rational, well‐defined reaction mechanisms opening the door to rational design of new MCRs with great efficiency.…”

“…[54,55] Despite the undeniable role of serendipity in MCR development, such observations significantly wane in attempts to afford high-order MCRs where rational design plays a significantly more important role. [56] Thus, with the advent of rational, well-defined reaction mechanisms opening the door to rational design of new MCRs with great efficiency. Along this line, the single reactant replacement (SRR) strategy allows farreaching development of novel MCRs.…”

Ugi Four-Component Reactions Using Alternative Reactants

“…The Ugi-4CR is taken into account as a crucial step in the production of various natural products [ 20 ]; for instance, the naturally potent α-amino acid antibiotic (+)-furanomycin II was prepared to utilize the Ugi-4CR [ 21 ]. In addition, many years of research investigation on this MCR have exhilaratingly culminated in the discovery of novel and effective synthetic methods for renowned drugs [ 22 , 23 ]. Ugi’s synthesis of the antibiotic penicillin through a highly convergent method is a beneficial example.…”

Organocatalytic skeletal reorganization for enantioselective synthesis of S-stereogenic sulfinamides

“…Over the past century, innovations of catalytic asymmetric synthesis have rapidly expanded the realm of accessible chiral chemical entities for pharmaceutical research [1][2][3] . Despite some impressive advances have been achieved, the breadth and depth of chiral skeletal diversification in discovery and development of new drugs are still constrained due to the unsolved problems in particularly important catalytic asymmetric transformations 4 .…”