I Like to Draw Pictures of Random Molecules

[DotChem]

inspired by the many thio on this page... thio 4-FPM ..

Now since sulfide are easily oxidized (even by simple exposure to ambient oxygen in air.. thio-4FPM-1-oxide:

Now this group (sulfoxide) looks like one found in modafinil type stimulants used by military..so could be good nootropic functional stim cross between FPM+Modafinil.. but who knows?
....for completion don't forget the S,S-dioxide:

nb: these are new untested compounds afaik (if you happen be in situation to be able to synthesize'em (pretty easy actually!) .. give me credit and send me my 3% patent royalties ..

 

[aspiringdrugdesign]

DotChem, perhaps a second phenyl group in a similar manner to modafinil would make it even more similar.

 

[DotChem]

^ Yes it would for sure where do you want to add extra phenyl? but you may loose 4-fluorophenmetrazine-like activity + increase lipophilicity

 

[aspiringdrugdesign]

I was thinking one carbon down from your sulfone group there, or perhaps replacing one of the ketones on the sulfur. Would that be too hindered if it were to replace a ketone?

 

[Solipsis]

Don't forget unifiram, although I guess that is different being a sulfonamide... Could trigger a sulfa allergy but not sure.

I think sulfones are bioisosteric to, if anything, ketones so a better analogue in the category perhaps would be:

1-methylaminoethyltol-4-ylsulfone (which prolly isnt iupac.. 1-methylaminotol-4-ylsulfonylethane then? ill settle for that).

"Ketone" applies to carbons (C=O), not to (other) heteroatoms.

@ADD: that would make it a hybrid which tend not to be winners at least when you make too big sacrifices and you often would in order to bridge that gap hybrids bridge. Also you can't replace a sulfone oxygen with a phenyl ring because it would not be a good valency for sulfur.

I love the sulfoxide / sulfone discussion Some of these may indeed be unrealistic due to the synthesis and I also guess unifiram is pricey for a reason?? But hey challenges are fun

 

[aspiringdrugdesign]

If sulfones are bioisosteric to ketones (now I know ketone only applies to oxygen), have any cathinone/sulfone derivatives been attempted? Is that still quite a difficult synthesis? I'm only finishing my first organic chem course, just touching on benzylic substitution right now.

Perhaps an alkene branch connecting the phenyl and sulfone then? It'd have to be two carbons long then though, that might change things.

I like these discussions too, it helps me learn more

 

[Pomzazed]

I studied JWH analogs during my master degree, the ones with sulfonyl(sulfone group), sulfinyl(sulfoxide group) are more prone to heat in comparison with parent carbonyl derivative, and likes to break into SO2 gas if trying to vaporize, in solution it is stable enough.

Synthesis is kinda straightforward but a little bit more steps than ketone, but that cant be discussed here.


PS. For these sulfur-y JWH analogs, I discourage anyone grabbing this idea for drug abuse purpose, it is unsafe regarding decomposition product and is not as efficient as ketone ones(per in vitro testing for binding).
PS2. The sulfide analog (just plain -S- linking) is prone to aerial oxidation, and parent molecule without alkyl tail on indole-1-position STINKS. (Similar to diphenylsulfide mixed with mothball and some dumpings)

 

[Solipsis]

If sulfones are bioisosteric to ketones (now I know ketone only applies to oxygen),

Not really, the term ketone applies to C=O specifically, not to be a stickler: the point is it refers more to the C= part than the oxygen, a thioketone is C=S not S=O. Has nothing to do with the isosterism

have any cathinone/sulfone derivatives been attempted?

Yes I recall that but it is not a public matter afaik nor was I interested to try

Perhaps an alkene branch connecting the phenyl and sulfone then? It'd have to be two carbons long then though, that might change things.

Am gonna go out on a limb here and say I think it would be unstable and have a tendency to polymerize.

Wow JWH compounds... both interesting and worrisome, toxicologically speaking a nightmare as far as RCs go: Hoffman may have decently studied his JWHs but the pharmacophore / general structure spawned an endless list of analogues involving all kinds of functional groups. I thought it was already both "brave" (fascinating I mean, also foolilsh) and reckless to guinea pig yourself when rather simple stim homologues etc became available many years ago, extending or swapping a group here and there hoping to make no significant toxicological changes. Cannabinoids are nuts in that regard and it is no surprise various are found to be toxic.

 

[Pomzazed]

^
Hehe by test i dont mean abuse or like, it was a proper academic study in university, but that was like many years ago.
I studied on the noncarbonyl bioisosterism of those compounds (including even C=S) The activity was tested using cultured cell lines.

What i said is (C=O) cannot be just swapped with (S=O), or (C=S) in every cases, if it functions as linker at that position its swappable, but once it contributes to binding there are some differences, the sulfinyl are Chiral group, with chiral center at S, and the =O and lone pair electron of S cant be flipped. The shape will be trigonal pyramid regarding to S, and carbonyl it is trigonal planar regarding to C. While thiocarbonyl is much more polarizable and it displays alot of (+)C—S(-) character instead of C=S

Interesting note is that the N-despentyl thiocarbonyl of JWH are deeply colored, and the solution turns from light yellow to deep red as concentration increases without transition via any orange color.

Isostere; is not always a fixed rulee that functional group A and be replaced by group B; depends on the molecule and how that position contributes to binding. For example in the case of modafinil, unlike my above examples, the S=O are replaceable by C=O and still retain quite some activity.

 

[Solipsis]

I know was more like.. speaking of which...

Hmm is the carbonyl of cathinones too involved with binding? I also don't know whether that different geometry would be permitted.

I don't ever see C=S in drugs or meds, is that typically metabolically safe?..

Uh I think that weirdly sometimes compounds are yellow when diluted in solution but red when concentrated, this even applies to certain yellow food pigments. I don't really know what could cause that, additive mixing of light for example can be really weird, sometimes when you see a color it is a product of two other colors mixing while the one you see is not emitted at all technically... the way our eyes work is particular.
Best explanation I have is that the red wavelengths with rising concentration add up way heavier than the yellow wavelengths when appearing darker, overwhelming simply because red is arbitrarily darker in our perception than yellow? - might be similarly true with bilirubine in urine though with brown?

Nope bioisosterism is not a rulee-fixe but compounds in this thread are so hypothetical that often predicting that stuff could go a bit far, though sometimes ppl like to go far with analysis because it is interesting or they feel like it

Chems right? Can't vacuum with them, can't be (and therefore not think) without them

 

[Pomzazed]

idk if thiocarbonyl is metabolically safe, I just tested in vitro.

Yellow to red in solution is not strange as the concentration rise, just lift up the amplitude of the wavelength, and the baseline will rise up and cover the other color, this applies to many red pigment (which diluted to yellow)

The weird thing is that my compound transit without orange in between, unlike most pigment.
This only happens in halogenated solvents like DCM or similar too, in toluene it has orange in the middle...

Interesting note is that thiocarbonyl of benzophenone is very deep blue, and transit to cyan without “light blue”inbetween too, when diluted with DCM. I GUESS it has something to do with the highly polarized C=S bond as (+)C—S(-) and the high dielectric constant of halogenated solvent! (No proof yet)


———
In cathinones, i think it involves, =O (or -OR, -OH) in beta position affects alpha1 and alpha2 binding, see adrenergic agents.

 

[DotChem]

I'm only finishing my first organic chem course, just touching on benzylic substitution right now.

May I suggest you take Biochem next: basic fundamental biochem like Lehninger Principles of Biochem dealing with proteins structure & function. It would be very useful if you plan career in medicinal chemistry/drug design in future.. good luck

Hmm is the carbonyl of cathinones too involved with binding? ..

Not critically afaik.. Prolintane (the fully reduced Pyrovalerone analog is as good stim as PV). But in that case tho, the carbonyl CO of PV is replaced by CH2. That doesn't affect binding but changes pharmacokinetics as one might expect: absorption, duration of effect, metabolism..etc since the molecule has now different physicochemical properties (ex: pKa of PV ~7.8-8; pKa prolintane ~10.2!! ).
As to replacing CO by SO2 in cathinones, I am not sure if alfa-aminosulfones are very stable: unlike RCO, RSO2 is a relatively good leaving group (in the form of RSO2- ; pKa of sulfinic acid usually < 5) so it would behave somewhat like an acyl aminal: NCHOAc very unstable in aq solution ).. but who knows? unless you make and test them!..

I don't ever see C=S in drugs or meds, is that typically metabolically safe?..? ..

There are few drugs having C=S for example: for example the one used to treat alcoholism, Disulfuram: pretty smelly, very nauseating shit.. but it works for compulsive binge drinkers. The C=S is actually pretty benign metabolically (not too hard on liver). It gets converted to C=O via first oxidation of the sulfur and 2. hydrolysis with a sulfonate as leaving group to give the corresponding ketone CO.

I studied JWH analogs during my master degree, the ones with sulfonyl(sulfone group), sulfinyl(sulfoxide group) are more prone to heat in comparison with parent carbonyl derivative, and likes to break into SO2 gas if trying to vaporize, in solution it is stable enough.

3-sulfonyl (as well as 3-acyl) N-unsubstituted indoles are pretty unstable in aq solution (especially in acidic media). Indoles behave like enamines: the 3 position is highly reactive towards electrophiles. It is very nucleophilic (and even more so for 3-acy or 3-sulfonyl): In aq sol , it would pick up a proton to give indolenium ion which may loose a proton to go back to starting acyl(sulfonyl) indoles or competing reaction the RCO (or RSO2) undergo attack by water to generate RCO2H or RSO3H and correspond deacetylated (desulfonated) indoles .. I wish I could draw pic w/ e flow to see what I am talking about.. but I am sure you get the point: My former boss was expert in indole chemistry. One the method is liked is protection indole 3-position by PhSO2 and then removed protecting group by mild acids once something done elsewhere. However, keep in mind, 3-acyl (or sulfonyl ) indoles are more stable when the indoles NH is substitued by alkyl, or acetyl..or tosyl..etc etc so the JW cannabis series should be ok since they all substituted on NH ..

 

[DotChem]

re: sulfone or sulfoxide bioisoteres. as ^^ mentioned, it all depends what one wants to achieve; sometimes it works sometimes not. With sulfo methadone for example ie Methiodone, it doesnt work that well. In that case the ketone CO of Methadone replaced by a Sulfone..
I've seen sulfones (SO2CH2CH3) used as bioisosters replacement of esters (CO2CH2CH3) where the issue is the ester susceptibility to hydrolysis (and hence shorter half-life) and the binding not that much affected.. talking about which makes me think of this:

or this

(nb: afaik these are new compound.. if you happen be in position access them.. give me credit and send me my 3% patent royalties

 

[pharmakos]

idk if thiocarbonyl is metabolically safe, I just tested in vitro.

Yellow to red in solution is not strange as the concentration rise, just lift up the amplitude of the wavelength, and the baseline will rise up and cover the other color, this applies to many red pigment (which diluted to yellow)

The weird thing is that my compound transit without orange in between, unlike most pigment.
This only happens in halogenated solvents like DCM or similar too, in toluene it has orange in the middle...

Interesting note is that thiocarbonyl of benzophenone is very deep blue, and transit to cyan without “light blue”inbetween too, when diluted with DCM. I GUESS it has something to do with the highly polarized C=S bond as (+)C—S(-) and the high dielectric constant of halogenated solvent! (No proof yet)


———
In cathinones, i think it involves, =O (or -OR, -OH) in beta position affects alpha1 and alpha2 binding, see adrenergic agents.

Perhaps the orange phase happens imperceptibly quick?

 

[aspiringdrugdesign]

May I suggest you take Biochem next: basic fundamental biochem like Lehninger Principles of Biochem dealing with proteins structure & function. It would be very useful if you plan career in medicinal chemistry/drug design in future.. good luck

I'm taking analytical chem and the second OChem class at my university next semester, I believe the biochem classes start the semester after that. It's my major after all!

 

[clubcard]

re: sulfone or sulfoxide bioisoteres. as ^^ mentioned, it all depends what one wants to achieve; sometimes it works sometimes not. With sulfo methadone for example ie Methiodone, it doesnt work that well. In that case the ketone CO of Methadone replaced by a Sulfone..
I've seen sulfones (SO2CH2CH3) used as bioisosters replacement of esters (CO2CH2CH3) where the issue is the ester susceptibility to hydrolysis (and hence shorter half-life) and the binding not that much affected.. talking about which makes me think of this:

or this

(nb: afaik these are new compound.. if you happen be in position access them.. give me credit and send me my 3% patent royalties

Use Chemaxiom to check cLogP and pKa values. The on-line version is free. Unless the molecule is uncharged at physiological pH then it won't cross the BBB and if the cLogP is low, it won't accumulate in the brain. ChemOffice allows you to overlay versions and Discovery Studio does the docking calculations.... oh, and Reaxys lets you know if it's already been tried....

But truly interesting. Sulfonate is generally a bioisostere of a ketone but a sulfone, due to the extra lone-pairs in S end up an odd shape... and are chiral.

 

[Soulfake]

A simple cocaine analogue with the tropane ring changed into norbornane:

 

[DotChem]

^ interesting ..

.. oh, and Reaxys lets you know if it's already been tried....

am afraid I can't afford the ~ US$20,000 Elsevier Co charge for access to Reaxys!!). Even if I do, I won't spend a penny since I don't think it is useful! Just waste of money (It is no better than pubmed literature search (ncbi.nlm.nih.gov) FREE and surechembl.org patent literature FREE! + uspto.gov FREE + .etc

 

[DotChem]

Dissociatives: this molecule is a potent NMDA antagonist which bind to PCP sites ..It is ~20x more potent than ketamine)! looks like pretty simple molecule but different from any other NMDA antagonist structure (legal or not..). Unless I miss something?

 

[clubcard]

^ interesting ..



am afraid I can't afford the ~ US$20,000 Elsevier Co charge for access to Reaxys!!). Even if I do, I won't spend a penny since I don't think it is useful! Just waste of money (It is no better than pubmed literature search (ncbi.nlm.nih.gov) FREE and surechembl.org patent literature FREE! + uspto.gov FREE + .etc

Reaxys is worth the money. What takes 5 minutes with can take 5 hours without. It is merely a question of how much your time is worth?

The sulfone substitutes in ketobemidone and it's x15 derivative. Finding the paper ON the FULL ketobemidone QSAR would be impossible without Reaxys because the titles of papers and patents nor keywords help. I suppose if you guessed the answer and searched of keywords, you might get lucky, but it is a British patent, so see if you can find it....

Sulfones also work in the cathinones. The twin problems are the synthetic cost and the lower LOogP... and unless you pack under dry nitrogen, they seem to polymerize.