1. milkshake on April 9, 2010 12:37 PM writes...

they should try to replace the ArNHSO2Ar' with benzyl sulfone ArCH2SO2Ar' or sulfoxide ArCH2SOAr'.

They can still go through the same sulfonyl chloride intermediate: stirring Ar'SO2Cl + aqueous Na2SO3 suspension at 40-60C gives Ar'SO2Na sulfinate solution (sometimes the sulfinate salt crashes out), addition of benzyl chloride or bromide with phosphate buffer and heating then produces sulfone in one pot procedure.

For sulfoxides, they can reduce their Ar'SO2Cl to thiol Ar'SH. Then alkylate on S with benzyl halide (K2HPO4 buffer added), then oxidize the thioether with 1 equiv of 50% hydrogen peroxide in formic-acetic acid 2:1 mix as a solvent at 0C, to get the sulfoxide.

There is a nice gentle way to reduce Ar'SO2Cl down to thiol Ar'SH: adding Ar'SO2Cl to 3.5 or 4 equivs of PPh3 in dichloromethane, then adding some water and refluxing the mix for about 1 hour on 50C bath. (Bu3P can be also used in the same way but PPh3 works fine for the purpose). To get rid of the spent phosphine/phosphinoxide crap, one dilutes the mix with ether and extracts the aryl thiol into aqueous phase with diluted KOH...
(But of course if LAH reduction is tolerable to the rest of the molecule it may be an easier alternative, with acid workup to liberate the thiol from the sats)

2. CRH on April 9, 2010 2:10 PM writes...

The benzyl sulfones are very prone to oxidation via P450 and then cleavage leaving the aldehyde and ArSO2H. If the NMe is tolerated, then the ArCHRSO2Ar' would be a viable option.

3. Anne on April 9, 2010 4:53 PM writes...

I'm so happy to see some dedicated work being done on these diseases. It's something I may be interested in working in eventually, but regardless of whether I personally get my hand in, I think it's so important for us to address these problems. Best of luck to this team.

4. milkshake on April 9, 2010 5:46 PM writes...

Also benzyl ethers ArCH(Me)OAr' sometimes work well for sulfanilide replacememnt - as CRH suggested it makes sense to put one methyl group into the benzylic position, to both restrict the conformation and to prevent oxidative debenzylation.

For an example of ArCH(Me)OAr' that originated from lead that was oxindole-sulfonyl anilide, look up the structure of PF-2341066, a c-Met cancer drug candidate, currently in phase III

5. John on April 10, 2010 5:51 PM writes...

An alpha ketoamide RCOCONR'2 sometimes works, see the JMC paper on HIV entry inhibitors publised by RJ Lu et al sometime in 2008 I think, they had some success the other way around looking at sulfonamide as a replacement for ketoamide as a patent busting strategy.

6. Pete on April 11, 2010 6:13 AM writes...

As well as having oral bioavailability and penetrating the CNS, the drug will also need to get into the trypanosome itself. I don’t know whether trypanosomes are more or less resourceful in responding to pharmaceutical challenges but I’d expect them to have some tricks up their sleeves.

From a quick look at the graphic of the protein-ligand complex, I’d guess that one ‘function’ of the methyls at C3 and C5 of the pyrazole is to lock what would be a relatively high energy conformation in their absence. It looks like the sulphonamide nitrogen is in contact with a water molecule and the key question if planning to methylate or replace with CH2 is how does that bound water molecule interact with the protein. Sulfonamides with heteraromatics attached to nitrogen can get quite acidic. I don’t think that the pKa of this one will be below normal physiological pH but it’s something to think about when developing SAR.

I think that the sulfone obtained by replacing the sulphonamide NH with CH2 would have good chance of getting into the bioactive conformation without the ‘help’of the C3 and C5 methyl groups although I’d want to look at the Cambridge Structural Database (CSD) for benzylphenyl sulfones to see if there was a strong tendency for the benzyl group to sit anti with respect to the phenyl. Although amides are significantly better hydrogen bond acceptors than ketones, sulfones are actually slightly better acceptors than analogous (tertiary) sulphonamides

Another option to at least think about would be to replace the sulphonamide nitrogen with oxygen. This may not be as outlandish as it sounds because, if memory serves me correctly, alkyl sulfonates hydrolyse by nucleophilic displacement of sulfonate from the alkyl. Clearly there are be things to be checked before diving in since somebody has probably measured hydrolysis kinetics for related model systems and there may well be relevant structures in the CSD.

7. Steve on April 12, 2010 10:43 AM writes...

I appreciate the comments folks. I have to say we did try out a number of these suggestions. The sulfones, although active, had high microsomal instability, the benzyl ethers were significantly less active. Alpha substitution may help in both these contexts...though we would not be too happy with chiral molecules. We attempted amides, and tried to induce a cis-like configuration with bulky alkyl groups. The sulfonamides do indeed have an appreciable pKa.

Sulfonates...interesting

8. milkshake on April 12, 2010 11:21 AM writes...

Sorry but medicinal chemist who says "we would not be happy with chiral molecules" when faced with one chiral center does not deserve to call himself a medicinal chemist, these days there are plenty decent asymmetric method around all that one needs to uase them is to buy a chiral HPLC column and spend just few weeks on trying some published methodology. In the meantime one can test the racemic compounds in vivo just to get an approximate idea.

Also microsomal stability data are often highly misleading, if this is what you are using (instead of the actual rat PK) to filter down your compounds, you are fools. Microsomal assay is only useful for identifying potential soft spots in the molecule and the main metabolites from oxidative degradation, it must not be used for ranking compounds "based on their metabolic stabuility"

9. Roland the Rapid Rat on April 12, 2010 3:22 PM writes...

Whoa, Milky you need to take a chill pill dude. Geesh maybe the guy has a good reason maybe they don't have chiral columns in Fundee. Sounds like you are perfect for a management position;)

10. milkshake on April 12, 2010 3:38 PM writes...

No - I know quite well how much extra work it takes if one has to do optically pure lead series because I was in that situation several times.

I think it is actually the Steve's position that is very management-like. When I was at Celera I heard the management tyoes repeatedly saying" We have to have a lead with microsomal stability above 30 min (half-time). We cannot have anything with active metabolites." They set up all these ideal-world scenarios in to their selection process, the wishful-thinking based requirements that were supposed to guarantee their fast progress but they did not really bother to check how many of the approved drugs would have actually gotten through their selection funnel... At the end they had no drug candidate.

A chiral HPLC reverse-phase column costs less than $1000 these days, and is hard to damage and uses acetonitrile-water with or without TFA so you dont even need to swich mobile phases on your HPLC. You don't even need a chiral HPLC from the beginning when you start with racemic series. Some of the asymmetric reactions are no more challenging than running borohydride reduction and you buy the catalyst from Strem. Many times one can actually buy the chirality in form of the optically-pure building block. And so on.

You know if they can't employ enough competent chemists maybe they should not dabble in medicinal chemistry at all. Maybe the grant money would be best left to some other research group.

11. Jose on April 12, 2010 5:11 PM writes...

I'd have to read "we would not be happy with chiral molecules" as implying "we would prefer to avoid them, but are not against it" FWIW.

12. fragment_boy on April 13, 2010 3:36 PM writes...

Reply to 10

Much as I agree that aggressive med chemists shouldnt fear a bit of chirality think you last paragraph is a bit OTT.....

You also have to bear in mind that I assume that as this is a neglected disease project, there are severe constraints on the final 'cost per dose'..... so a fancy chiral molecule may be all and well but if it pushes the manufacturing cost up then its still a loss..

13. sepisp on April 26, 2010 5:24 AM writes...

#12 fragment_boy: Isn't your opinion the same as "optimizing before compiling" in programming?

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