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DBL%20Hendrix%20small.png College chemistry, 1983

Derek Lowe The 2002 Model

Dbl%20new%20portrait%20B%26W.png After 10 years of blogging. . .

Derek Lowe, an Arkansan by birth, got his BA from Hendrix College and his PhD in organic chemistry from Duke before spending time in Germany on a Humboldt Fellowship on his post-doc. He's worked for several major pharmaceutical companies since 1989 on drug discovery projects against schizophrenia, Alzheimer's, diabetes, osteoporosis and other diseases. To contact Derek email him directly: derekb.lowe@gmail.com Twitter: Dereklowe

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In the Pipeline: Don't miss Derek Lowe's excellent commentary on drug discovery and the pharma industry in general at In the Pipeline

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September 7, 2011

Get Yer Rhodanines Here

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Posted by Derek

We've talked here before about the structural class known as rhodanines - the phrase "polluting the scientific literature" has been used to describe them, since they rather promiscuously light up a lot of drug target assays, and almost never to any useful effect.

Well, guess what? Now there's an even easier way to make them! And says this new paper in the Journal of Organic Chemistry:

5-(Z)-Alkylidene-2-thioxo-1,3-thiazolidin-4-ones (rhodanine derivatives) were prepared by reaction of in situ generated dithiocarbamates with recently reported racemic α-chloro-β,γ-alkenoate esters. This multicomponent sequential transformation performed in one reaction flask represents a general route to this medicinally valuable class of sulfur/nitrogen heterocycles. Using this convergent procedure, we prepared an analogue of the drug epalrestat, an aldose reductase inhibitory rhodanine.
Sequentially linking several different components in one reaction vessel has been studied intensively as a rapid way to increase molecular complexity while avoiding costly and environmentally unfriendly isolation and purification of intermediates.(1-4) Such efficient multicomponent reactions, such as the Ugi reaction, often produce privileged scaffolds of considerable medicinal value. Rhodanines (2-thioxo-1,3-thiazolidin-4-ones) are five-membered ring sulfur/nitrogen heterocycles some of which have antimalarial, antibacterial, antifungal, antiviral, antitumor, anti-inflammatory, or herbicidal activities. . .In conclusion, convergent syntheses of N-alkyl 5-(Z)-alkylidene rhodanine derivatives have been achieved using recently reported racemic α-chloro-β,γ-alkenoate ester building blocks. The formation of these rhodanine derivatives involves a three-step, one-flask protocol that provides quick access to biologically valuable sulfur–nitrogen heterocycles.

Just what we needed. Now it's only going to be a matter of time before someone makes and sells a library of these things, and we can all get to see them again as screening hits in the literature.

Comments (11) + TrackBacks (0) | Category: Chemical News | Drug Assays


COMMENTS

1. Hap on September 7, 2011 12:30 PM writes...

"But the assays say they do everything! They can't all be worthless."

Yes, and you can probably get some tasty fish in the Kill Van Kull, too. It's just a matter of finding one in the...water there.

Permalink to Comment

2. PharmaHeretic on September 7, 2011 1:08 PM writes...

According to them- "some of which have antimalarial, antibacterial, antifungal, antiviral, antitumor, anti-inflammatory, or herbicidal activities"

I think we know where that leads.. but at least somebody is making money out of this BS.

Permalink to Comment

3. anchor on September 7, 2011 2:20 PM writes...

Coming from a reputable is even bigger surprise! I am sure that Prof. Gary Posner is aware of promiscuity of this dye.

Permalink to Comment

4. Hap on September 7, 2011 2:29 PM writes...

Probably, but it seems misleading to talk about the potential biological uses and benefits of the rhodanines when they are known to be highly problematic and that most of their unambiguous known biological effects involve making medicinal chemists (more) crazy and to make assays light up like menorahs. There could be lots of uses for rhodanines, but as a privileged scaffold doesn't seem like one of them.

At least this didn't come ten years earlier.

Permalink to Comment

5. Ed on September 7, 2011 3:55 PM writes...

In defense of Gary Posner who published this paper, I don't think it is a valid argument to say that rhodanines are useless or that a new way of making them is useless when there are in fact marketed drugs that are rhodanines.

Permalink to Comment

6. SP on September 7, 2011 4:08 PM writes...

Clearly the assay of clinical efficacy is just another artifact.
The whole PAINs phenomenon, just like the various rules of n, is being oversimplified. It was a computational paper that said, "Hey, these things hit often and usually don't pan out." It didn't say they never pan out, and tossing them out of hand may or may not lead to a false negative. As with all HTS, it's a probability game- there's a good chance you're following up on artifacts, but not a 100% chance, so do you want to roll the dice?

Permalink to Comment

7. DannoH on September 7, 2011 4:18 PM writes...

Am I the only one who is tired of certain centers of academic research that feel compelled to insist that "The" is inserted prior to "" in any and all speaking, written, or televised reference to said university?

Permalink to Comment

8. Dennis on September 8, 2011 10:02 AM writes...

DannoH: And if there are so many of these Johns, which one is "The" one anyways?

Permalink to Comment

9. Hap on September 8, 2011 11:57 AM writes...

Would I rather go fishing in Montana or in the Thames? Where am I more likely to find (edible) fish?

If you can make enough rhodanines, you can characterize their structure-activity relations in various assays and potentially determine what makes them liable to misbehave and thus figure out which ones might be useful. Since, however, it seems like making crap and sorting it later pays the same...

Permalink to Comment

10. another medicinal chemist on September 9, 2011 3:42 AM writes...

Derek,
Rather than criticizing Posner and co-workers for developing an improved synthesis of rhodanines, why don’t you just stop screening these compounds?

Permalink to Comment

11. Tyrosine on September 20, 2011 11:27 PM writes...

"Rhodanine as a Privileged Scaffold in Drug Discovery" DOI: 10.2174/092986709788186200

They must be good :-)

Permalink to Comment

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