There's a new paper coming to the defense of rhodanines, a class of compound that has been described as "polluting the scientific literature". Industrial drug discovery people tend to look down on them, but they show up a lot, for sure.
This new paper starts off sounding like a call to arms for rhodanine fans, but when you actually read it, I don't think that there's much grounds for disagreement. (That's a phenomenon that's worth writing about sometime by itself - the disconnects between title/abstract and actual body text that occur in the scientific literature). As I see it, the people with a low opinion of rhodanines are saying "Look out! These things hit in a lot of assays, and they're very hard to develop into drugs!". And this paper, when you read the whole thing, is saying something like "Don't throw away all the rhodanines yet! They hit a lot of things, but once in a while one of them can be developed into a drug!" The argument is between people who say that elephants are big and people who say that they have trunks.
The authors prepared a good-sized assortment of rhodanines and similar heterocycles (thiohydantoins, hydantoins, thiazolidinediones) and assayed them across several enzymes. Only the ones with double-bonded sulfur (rhodanines and thiohydantoins) showed a lot of cross-enzyme potency - that group has rather unusual electronic properties, which could be a lot of the story. Here's the conclusion, which is what makes me think that we're all talking about the same thing:
We therefore think that rhodanines and related scaffolds should not be regarded as problematic or promiscuous binders per se. However, it is important to note that the intermolecular interaction profile of these scaffolds makes them prone to bind to a large number of targets with weak or moderate affinity. It may be that the observed moderate affinities of rhodanines and related compounds, e.g. in screening campaigns, has been overinterpreted in the past, and that these compounds have too easily been put forward as lead compounds for further development. We suggest that particularly strong requirements, i.e. affinity in the lower nanomolar range and proven selectivity for the target, are applied in the further assessment of rhodanines and related compounds. A generalized "condemnation" of these chemotypes, however, appears inadequate and would deprive medicinal chemists from attractive building blocks that possess a remarkably high density of intermolecular interaction points.
That's it, right there: the tendency to bind off-target, as noted by these authors, is one of the main reasons that these compounds are regarded with suspicion in the drug industry. We know that we can't test for everything, so when you have one of these structures, you're always fearful of what else it can do once it gets into an animal (or a human). Those downstream factors - stability, pharmacokinetics, toxicity - aren't even addressed in this paper, which is all about screening hits. And that's another source of the bad reputation, for industry people: too many times, people who aren't so worried about those qualities have screening commercial compound collections, come up with rhodanines, and published them as potential drug leads, when (as this paper illustrates), you have to be careful even using them as tool compounds. Given a choice, we'd just rather work on something else. . .