Recent developments with rhodanine as a scaffold for drug discovery

ABSTRACT

Introduction: Rhodanines, as one of the 4-thiazolidinones subtypes, are recognized as privileged heterocycles in medicinal chemistry. The main achievements include the development of drug-like molecules with numerous biological activities as well as approved drugs. Among rhodanines, 5-ene-rhodanines are of special interest, and are often claimed as pan assay interference compounds due to Michael acceptor functionality.

Areas covered: Herein, the synthetic protocols for rhodanines and their transformation are reviewed. Biological activity is briefly discussed as well as biotargets, mode of actions and optimization directions. Furthermore, the utilization of 5-ene-rhodanines in Michael additions are discussed while both pro and contra arguments have been outlined within medicinal chemistry application.

Expert opinion: Rhodanines remain privileged heterocycles in drug discovery. They are accessible building blocks for optimization and transformation into related heterocycles, simplified analogues and fused heterocycles with a thiazolidine framework. Michael acceptor functionality, as well as the thesis about low selectivity towards biotargets of rhodanines, must be confirmed experimentally and it cannot be based on just the presence of conjugated α,β-unsaturated carbonyl. Moreover, the positive aspects of Michael acceptors must be considered as well as their multitarget properties. New criteria for target affinity must be found. In conclusion, rhodanines are generally not problematic per se.

KEYWORDS:

• Rhodanine
• 4-thiazolidinone
• Michael acceptor
• PAINS

Article highlights

• Rhodanines possess a variety of biological activities (both in screening campaigns and directed experiments) and are considered as a tool for synthesis of related thiazolidinones, simplified analogs and diversity complex heterocycles within various approaches.

• Among rhodanine subtypes 5-ene-rhodanines and rhodanine-3-carboxylic acids are of special interest as hit- and lead-compounds with anticancer, antimicrobial, antiviral, antidiabetic etc. activities.

• Rhodanines and related thiazolidinones (2-amino(imino)-, 2-R- and 2-ene-4-thiazolidinones, isorhodanines, 2,4-thiazolidinediones etc.) are often considered as bioisosteric compounds.

• Assigning 5-ene-rhodanines as pan assay interference compounds (PAINS) due to their possible Michael acceptor functionality, they should be analyzed in depth: experimental confirmation is essential to claim target compounds as PAINS; the positive aspect of such covalent modifiers should not be discarded.

• Low selectivity of rhodanines against biotargets as well as toxicity data should always be evaluated but not predicted or assumed based on the affiliation to 5-ene-rhodanine derivatives.

• Rhodanines are often effective tools for medicinal chemistry and should not be regarded as useless per se.

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Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

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Funding

This manuscript has not been funded.