Privileged Scaffolds or Promiscuous Binders: A Comparative Study on Rhodanines and Related Heterocycles in Medicinal Chemistry

Abstract

Rhodanines and related five-membered heterocycles with multiple heteroatoms have recently gained a reputation of being unselective compounds that appear as "frequent hitters" in screening campaigns and therefore have little value in drug discovery. However, this judgment appears to be based mostly on anecdotal evidence. Having identified various rhodanines and related compounds in screening campaigns, we decided to perform a systematic study on their promiscuity. An amount of 163 rhodanines, hydantoins, thiohydantoins, and thiazolidinediones were synthesized and tested against several targets. The compounds were also characterized with respect to aggregation and electrophilic reactivity, and the binding modes of rhodanines and related compounds in published X-ray cocrystal structures were analyzed. The results indicate that the exocyclic, double bonded sulfur atom in rhodanines and thiohydantoins, in addition to other structural features, offers a particularly high density of interaction sites for polar interactions and hydrogen bonds. This causes a promiscuous behavior at concentrations in the "screening range" but should not be regarded as a general knockout criterion that excludes such screening hits from further development. It is suggested that special criteria for target affinity and selectivity are applied to these classes of compounds and that their exceptional and potentially valuable biomolecular binding properties are consequently exploited in a useful way.

Identification and Characterization of Novel Inhibitors of Mammalian Aspartyl Aminopeptidase

“…Based on steric considerations, we hypothesize that rhodanine is more likely to interact with the binuclear center of DNPEP via its exocyclic rather than endocyclic sulfur atom. Density function theory calculations predict that the highest occupied molecular orbital and negative electrostatic potential of the rhodanine ring localize predominantly to the exocyclic sulfur atom (Mendgen et al, 2012), which supports the proposed role of this site in metal coordination. Compound 347749 can be modeled into the DNPEP active site in a sterically acceptable fashion with the exocyclic sulfur binding in the bridging ligand position between the zinc ions and the negatively charged theoninyl side chain occupying the S1 pocket via an ionic interaction with Lys 370 and hydrogen-bonding interactions with surrounding protein groups.…”

“…2010; Mendgen et al, 2012). This compound is reportedly able to bind molecules in a promiscuous fashion leading to nonselective effects (Baell, 2010).…”

“…Compound 769078 represents group C dual inhibitors containing a rhodanine moiety linked to furan ring by an alkene spacer. Rhodanine is a known pan assay-interference moiety (Mendgen et al, 2012) that has been reported active in a significant number of HTS assays, causing concerns about the specificity of compounds containing this chemical group (Carter et al, 2001;Voss et al, 2003;Carlson et al, 2006;Powers et al, 2006;Baell and Holloway, 2010). However, these compounds share the common features seen in other DNPEP inhibitors with two functional groups bridged by four to six covalent bonds, suggesting that they could exert a DNPEP-selective effect with further modifications.…”

Small Molecule Screening Identifies Regulators of the Transcription Factor ΔFosB

“…3,47 However, upregulating ΔFosB activity in a brain region specific way may also prove useful to enhance endogenous resilience mechanisms to combat depression. 6 While developing five-membered multiheterocyclics into drugs may be a long-term endeavor, 48,49 C2 and C6 can already be used as chemical tools, by administering them directly into the brain to tease apart the role of ΔFosB in repressive as well as activational transcriptional complexes and to assess the epigenetic state of its different target genes during maladaptive neural changes. Such molecular insight could guide assessment of the therapeutic utility of ΔFosB.…”

Screening of the antiviral activity in the range of C5 and N3 substituted 4-thiazolidinone derivatives

“…It should be also noted that 5-ylidene-4-thiazolidinone-3-carboxylic acids are among the preferred hitcompounds when using various in silico approaches with the subsequent experimental confirmation of the high affinity level to numerous biological targets [9]. Such findings are often criticized because of reffering 4-thiazolidiones to the so-called "frequent hitters" or "pan assay interference compounds (PAINS)" ("frequent hits" are compounds assigned as high-affinity ligands to the set of biotargets and tend to have a low specificity) [5,10,11]. Although, the debate of the importance of such approach remains open.…”