There’s an interesting article coming out in J. Med. Chem. on antibiotic compounds, which highlights something that’s pretty clear if you spend some time looking at the drugs in that area. We make a big deal (or have made one over the last ten years) about drug-like properties – all that Rule-of-Five stuff and its progeny. Well, take a look at the historically best-selling antibiotic drugs: you’ve never seen such a collection of Rule of Five violators in your life.
That’s partly because a lot of structures in that area have come from natural products, but hey, natural products are drugs, too. Erythromycin, the aminoglycosides, azithromycin, tetracycline: what a crew! But they’ve helped an untold number of people over the years. It’s true that the fluoroquinolones are much more normal-looking, but those are balanced out by weirdo one-shots like fosfomycin. I mean, look at that thing – would you ever believe that that’s a marketed drug? (And with decent bioavailability, too?)
No, you have to be broad-minded if you’re going to beat up on bacteria, and I think some broad-mindedness would do us all good in other therapeutic areas, too. I don’t mean we should ignore what we’ve learned about drug-like properties: our problem is that we tend to make allowances and exceptions on the greasy high-molecular weight end of the scale, since that’s where too many of our compounds end up. It wouldn’t hurt to push things on the other end, because I think that you have a better chance of getting away with too much polarity than you have of getting away with too little.
One reason for that might be that there are a lot of transporter proteins in vivo that are used to dealing with such groups. It’s easy to forget, but a great number of proteins are decorated with carbohydrate residues, and they’re on there for a lot of reasons. And a lot of extremely important small molecules in biochemistry are polar as well – right off the top of my head, I don’t know what the logD or polar surface area of things like ATP or NAD are, but I’ll bet that they’re far off the usual run of drugs. Admittedly, those aren’t going to reach good blood levels if you dose them orally; we’re trying to do something that’s rather unnatural as far as the body’s concerned. But we could still usefully take advantage of some of the transport and handling systems for such molecules.
But that’s not always easy to do. We all talk about making our compounds more polar and more soluble, but we balk at some of the things that will do that for us. Sure, you can slap a couple of methoxyethoxys on your ugly flat molecule, or hang a morpholine off the end of a chain to drag things into the water layer. But slap five or six hydroxyls on your molecule, and you’ll be lucky not to have the security guards show up at your desk.
There are, to be sure, some good reasons why they might. Hydroxyls and such tend to introduce chiral centers, which can make your synthesis difficult and dramatically increase the amount of work needed to fill out the structural possibilities of your lead series. That’s why these things tend to be (or derive from) natural products. Some bacterium or fungus has done most of the heavy lifting already, both in terms of working out the most active isomers and in synthesizing them for you. Erythromycin’s a fine starting material when you can get it by fermentation, but no one would ever, ever consider it if it had to be made by pure total synthesis.
There’s another consideration, which gets you right at the bench level. For an organic chemist, working with charged, water-soluble compounds is no fun. A lot of our lab infrastructure is built for things that would rather dissolve in ethyl acetate than water. A constant run of things with low logD values would mean that we’d all have to learn some new skills (and that we’d all probably have to spend a lot of time on the lyophilizer). Ion-exchange resins, gel chromatography, desalting columns – you might as well be a biochemist if you’re going to work with that stuff. But in the end, perhaps we might be better off, at least part of the time, if we were.