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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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March 9, 2012

Double-Bond-S

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Posted by Derek

The carbonyl group is one of the most fundamental structure in organic chemistry: C-double-bond-O. But you can substitute that oxygen with a sulfur and get to a whole new series of compounds - so how come we don't see so many of those in drugs?

Well, not all of them are stable. Plain old thioketones are pretty reactive, not to mention their appalling stink. And even though they're not as bad as thioketones, the corresponding thioamides and thioureas are known to be more lively than their oxygen counterparts. Many medicinal chemists avoid them because of a reputation for trouble, which I think is probably earned and not just an irrational prejudice. But there are drugs and pharmacological tools with these structures, still.

The thiocarbonyl shows up in a number of heterocycles, too, and there the situation gets a bit murkier. The highest-profile member of this group, unfortunately, may well be the rhodanines, which have come up several times on this blog, most recently here. I'm not a fan of those guys, but here's a question: are there thiocarbonyl structures that are better behaved? Do people like me look down on the whole functional group because of a few (well, more than a few) bad actors?

Comments (27) + TrackBacks (0) | Category: Life in the Drug Labs


COMMENTS

1. Rick Wobbe on March 9, 2012 9:20 AM writes...

Sulfur's fundamental differences from O - electronegativity, ionization energies, molecular orbital possibilities to name a few - probably limit its utility in many cases. But, as suggested in a recent post here, empiricism dominates more often than we'd like to admit, so let the experiments flow...

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2. sinpl on March 9, 2012 9:36 AM writes...

There are two in thioridazine, a major tranquillizer in the 80s, especially in the US. I'd guess that the heterocyclic one is less reactive, the sulfoxide is a known by-product.

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3. Rick Wobbe on March 9, 2012 9:42 AM writes...

On a related note, why not more Si in drugs in place of C?

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4. David Borhani on March 9, 2012 9:57 AM writes...

@ #2, sinpl, thioridazine doesn't have the C=S group; rather it has a phenothiazine (common in such drugs) and a thioether (less common).

Methimazole (a.k.a. tapazole, 1-methyl-3H-imidazole-2-thione) and the related drug propylthiouracil, used to treat hyperthyroidism, are both associated with a significant rate (0.1 - 0.5%) of serious side effects, such as agranulocytosis and hepatitis.

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5. Curious Wavefunction on March 9, 2012 10:11 AM writes...

I would think that at least part of the reason would concern the lack of hydrogen bonding potential of C=S groups compared to their C=O counterparts (in fact, are C=S...H-N hydrogen bonds known at all?).

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6. anon the II on March 9, 2012 10:13 AM writes...

Tolrestat had a thioamide which I believe was much better than the amide but I can't remember why. Maybe oral bio-availablilty. It's an aldose reductase inhibitor which was approved for diabetes complications. Never made it in the US and was eventually withdrawn for tox reasons.

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7. A Nonny Mouse on March 9, 2012 10:15 AM writes...

#3 Quick breakdown of silicon drugs

http://www-anorganik.chemie.uni-wuerzburg.de/forschungsgruppen/prof_dr_r_tacke/arbeitsgebiete/silicon_containing_drugs/disila_bexarotene/

We have a group a Wellcome that was trying to take a thioscemicarbazide through for AIDS- unfortunately is was an "everything-icide" and was quietly dropped. I believe something similar was later "rediscovered" at Xenova.

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8. milkshake on March 9, 2012 10:16 AM writes...

thioureas are generally toxic and possess metal coordinating properties. I suppose you can get away with it if the active dose is low enough - one example sodium thiopental

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9. anon2 on March 9, 2012 10:20 AM writes...

The sniff of a thiol odor, which can be quite common, is a compound killer.

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10. Just Sayin' on March 9, 2012 10:27 AM writes...

Aren't thiocarbonyls more prone to hydrolysis? On a side note, I worked with thioethers that didn't smell too bad...one even had hints of basil and cilantro!

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11. Andrés on March 9, 2012 10:31 AM writes...

I had the chance to work with thiono-beta-lactams. A colleague of mine prepared the "thiono-variant" of a pre-existing library of immobilized monocyclic beta-lactams. Those compounds were very nice and easy to synthesize utilizing Lawesson's reagent. I synthesized thiono-PenV and thiono-cephalosporins in the solution phase. That was quite awful. Isn't recomendable. It's all published, none of the compounds were tested for activity.

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12. CanChem on March 9, 2012 10:44 AM writes...

In an antibiotic program I worked on we tried a systematic O-->S switch on the C=O's of a uracil-like ring system. Synthesis was a bit tricky, but not impossible, but we lost all activity (combination of increased steric bulk, decreased H-bonding, and increased greasiness).

I've also tried swapping in thioethers for ethers, but had problems with oxidation in those substrates. So all in all, useful for academic exercises, but never found any candidates doing that.

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13. Moody Blue on March 9, 2012 11:30 AM writes...

I have also thought that thiocarbonyls are avoided in drugs due to toxicity associated with them. Thus I was surprised to see structures like that of Elesclomol make into clinicals. Also, some years ago, while working on Met inhibitors, I was surprised to see few companies making several analogs of thioamides and thioureas on quinoline, quinazoline scaffolds. Of course, they were all following examples from a certain beer company in Japan, which apparently has interest in making drugs.

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14. Thyroid on March 9, 2012 11:32 AM writes...

Thioamides can inhibit TPO, which is one source of their tox issues.

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15. S= hater on March 9, 2012 2:51 PM writes...

Nasty unstable things that do unwanted things
in bioassays... nearly as bad as thioethers off a nitrogen-containing heterocycle. We slung 'em out of the screening collection and never missed 'em.

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16. Toad on March 9, 2012 5:47 PM writes...

There are always exceptions to the rules, but if you look at correlations of functional groups with toxicology results, thiocarbonyl compounds show an extremely high propensity to elicit toxic effects in cells/animals/trials compared to other functional groups or med chem moieties. I believe Nick Meanwell at BMS has some good compilations of these data.

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17. partial agonist on March 9, 2012 6:31 PM writes...

Nothing good is going to happen if you pay too much attention to those C=S containing hits

A thiourea mow and then will SEEM interesting but

as David Byrne of the Talking Heads said,

you better run, run,
run run away....

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18. Sulfoxides on March 9, 2012 8:31 PM writes...

Sulfoxides (RSOR') also have a nasty little detail... they're chiral.

So if you replace a ketone on a chiral molecule with a sulfoxide, you now have 2 diastereomers to deal with, and it can often be difficult to find conditions that affect the ratio of diastereomers.

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19. Sulfoxides on March 9, 2012 8:32 PM writes...

Sulfoxides (RSOR') also have a nasty little detail... they're chiral.

So if you replace a ketone on a chiral molecule with a sulfoxide, you now have 2 diastereomers to deal with, and it can often be difficult to find conditions that affect the ratio of diastereomers.

Permalink to Comment

20. Sulfoxides on March 9, 2012 8:33 PM writes...

Sulfoxides (RSOR') also have a nasty little detail... they're chiral.

So if you replace a ketone on a chiral molecule with a sulfoxide, you now have 2 diastereomers to deal with, and it can often be difficult to find conditions that affect the ratio of diastereomers.

Permalink to Comment

21. gippgig on March 9, 2012 11:06 PM writes...

Methylcoenzyme M reductase contains (along with some other weird posttranslational modifications) a thioglycine - yes, S is substituted for O in the main polypeptide chain.

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22. gippgig on March 10, 2012 12:13 AM writes...

Oops, I forgot that the antibiotic thiopeptin contains a similar thioamide. (It doesn't appear to be involved in activity; other closely related antibiotics such as thiostrepton lack it.)

Permalink to Comment

23. medchemist on March 10, 2012 8:49 AM writes...

here's a decent looking thiolactam compound:
http://pubs.acs.org/doi/abs/10.1021/jm2011172

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24. Mimer on March 10, 2012 5:50 PM writes...

Thiocarbonyls spell problems in drugs since they are prone to reactive metabolite (RM) formation. The mechanism of thiourea toxicity is well explained since long and the attempt to use thiourea in, for example, the H2 antagonist metiamide was unfortunate. For a collation on reviews, and more, in the RM field see http://www.stoprm.org/

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25. anono on March 11, 2012 1:27 PM writes...

Interested to hear of thiocarbonyls that are particularly unstable or difficult to make...

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26. sjb on March 12, 2012 5:49 AM writes...

@Sulfoxides = oh I dunno, I thought Sharpless' conditions worked quite well for these things?

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27. NorthwesternChemist on March 12, 2012 5:02 PM writes...

sulazepam is an analog of diazepam, the only difference is the C=S replacing the C=O. Under the right circumstances they can certainly be interchanged.

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