Certainly flat, maybe not pretty, and probably not particularly soluble. At least they’ve got a sense of humor and they’ll need it if they try to take this monstrosity anywhere. Will the aniline derived from the urea give a positve Ames test? Maybe not if it won’t go into solution. Perhaps some hERG from the cation and then all the usual big flat molecule stuff. Still if this sort of thing turns you on, why not visit:
CUTE!!! I could maybe do some interesting things with the badass little chromophore in the middle, plus another ring or two…
I don’t see why it wouldn’t be soluble in organics, though. I’d think maybe the benzene ring would be a little twisted out of plane, and in any case, the other substituents should serve to hold the molecules far apart enough to break up the pi-stacking a little…in any case, IIRC, things don’t REALLY turn into brickdust until you have 4+ish fused rings. 🙂 Soluble in water? IDK, I see a lot of nitrogen, and parts of it look pretty polar, so there’s no telling what it could do at the right pH. (Not that I know anything about drug design–I’m on the other side of the carbon universe.)
I trust that kinasepro is honored to have Ψ*Ψ, the renowned blogger, commenting on the offerings. She is right about the pH and solvent although I’d guess that solubility in organic solvents will still not be great although it should be better than the aqueous solubility. Much though we would like to control both pH and solvent for some of our less popular patients, neither are clinical options. I presume that the offending pharmaceutical company is less pleased to have the materials potential for their drug discussed in this forum. Which of course is an excellent reason to do so.
In response to Ashutosh’s comment, urea’s do have a greater tendency to go cis, especially when you’ve got a nearby hydrogen bond acceptor. I seem to remember acyl ureas going cis ‘naturally’ although best to check the CSD because I’ve not looked at these for a while.
Ψ*Ψ: N,N’-diaryl ureas somehow don’t have much enegy difference between the trans-trans and trans-cis arrangement. I don’t know why this is so but I have seen the same thing in X-ray of our compounds bound to a protein.
Amd in the above case the trans-cis is even stabilized, by the H-bond.
A hydrogen bonded cis urea is likely to be very flat. Let’s take a look at the relationship between the benzene ring and the fused heterocycle. If memory serves me correctly, the minimum energy for biphenyl has the rings twisted by about 40 degrees with respect to each other. The benzene ring in the monstrosity sees a 5 rather than 6-membered ring and one with a doubly connected nitrogen next to the link. Both of these factors will reduce the minimum energy angle between the rings as well as the strain energy of achieving local planarity.
I guess it’s possible that the urea would lie flat in the plane of the benzene ring…in N-phenyl substituted perylene diimides, though, which are maybe more rigid, the phenyl substituent is held at a pretty severe angle. In any case, y’all can’t tell me the t-butyl group will be flat. 😉
Is there a crystal structure of this or something like it floating around?
OPLS_2005 and MMFFs do not give any significant energy diff (<5 kJ/mol) either for the simple unsubstituted biphenyl or for the molecule above (that is, there is negligible energy difference between the constrained-optimized structure and the unconstrained-optimized structure) For the biphenyl with an ortho-methyl of course, there is a huge energy difference, with the optimum angle between the rings being 60 degrees. So for the molecule there should not be much problem for achieving planarity.
P.S. Force fields are usually pretty well-parametrized for reproducing steric effects.
Seconding milk’s point, the energy difference between say transtrans and transcis N N’-diphenyl urea with a good level of theory is about 1-2 kcal/mol. Plus, the protein would change things often.
I think of the relative orientation of linked aromatic rings as stereoelectronic rather than steric and I’m wary of what the force fields say for anything other than biphenyl. Take a biphenyl and put dimethylamino at C4 and nitro at C4′. Does the force field know? Does the force field even care? Generally the CSD is my first port of call when trying to understand conformations but even with that you’ve got to be careful. If you can’t find the answer there, do you belive the force field?
The tBu will obviously not be flat and in fact neither will the piperazine. Nevertheless, the molecule will be able to present a large, planar chunk (probably not the right word here) to proteins that you’d prefer they didn’t.
Finally, may I suggest the number of times that Ψ*Ψ comments on a molecule be adopted as an undruglikeness metric.
GMC, you’re probably right 😉 my interests are pretty far from drugs. I’d be interested in functionalizing a larger version of the little aromatic beastie in the middle, if heterocycles didn’t have it in for me.
Heh, well I’ve turned my visual bioavailabrator off because its wrong about 94 % of the time… That said though, the imidazobenzimidazole doesn’t scare me too much, and the fact that the urea is tied up makes me feel ok about that end too…
As MS mentioned ‘tied back’ acyl ureas are precedented, and this fits that mold imo. pyridyl ureas too check 1GII
Well, it depends on what we mean when we ask if the force field cares or not. MMFF and OPLS_2005 use a very large database of molecules for parametrization. As I said before, the one thing that’s supposed to be treated well by FFs in general is steric effects. FFs are worse at handling electrostatics, especially in case of multipolar molecules. In the case of a phenyl ring bonded to an oxazoline, through space electrostatic effects probably won’t be a problem. The general rule about FFs is that they do a pretty good job of optimizing geometries, but a relatively poor job of giving energies because of the dominance of electrostatic terms. In any case, any calculation for a molecule should always be checked against an ab intio one using a good level of theory, and therein is part of the answer about whether we should believe a force field or not.