The Half Decent Pharmaceutical Chemistry Blog

Good evening and welcome! This week, one of the posts outlined an important feature of physostigmine, so, I've decided to complete the cycle by making of atropine, an important antidote of the aforementioned AChE inhibitor, the protagonist of tonight's SNS.

Atropine is one of the first drugs in the history: a great cosmetic for women, a reliable poison for men and women who had enemies (mm, sounds interesting...). It still has to be considered the leading compound in the design of most of muscarinic antagonists.
Moreover, the drug can be used as a mydriatic or to treat bradycardia, poisoning with AChE inhibitors (including some of those you can find in chemical weapons) and muscarine-producing mushrooms.

Although we are about to start synthesizing it, it has to be said that atropine can be found in fascinating Atropa Belladonna (one of the best-looking plants I've ever seen). Only the levo enantiomer, which is the active one, but the base used for the extraction deprotonates the chiral carbon and, due to the position of the ester, you'll certainly understand while you always get the chiral mixture.

Let's take a look at this (total) synthesis.



The first part of the synthesis begins with phenylacetic acid: two equivalents of a Grignard reagents, basically, are used in a quite uncommon acid-base reaction. We complete the synthesis of tropic acid with formaldehyde and hydrochloric acid. The product will obviously have to undergo chiral resolution, since we need L-hyoscyamine only.

Now let's start to discuss the cool stuff.
An acetal of succinic aldehyde is opened and treated with methylamine and acetone dicarboxylic acid. I must say, I like the proposed mechanism very much and it's, to be honest, the reason why I chose this very synthesis, this week.
I mean, one of my professors of organic chemistry used to say he didn't believe in most of proposed mechanisms (especially when it comes to name reactions). Here I find it extremely plausible, considering that water and CO2 are released.

By the way, after this superb mechanism, we end up with tropinone: hydrogenation will yield two geometric isomers, pseudotropine (which isn't needed) and tropine, we must separate.

Finally, tropine reacts with the tropic acid and we yield atropine, or, to be precise, L-hyoscyamine.

Entamoeba histolytica is a pretty vicious protozoan. It can cause asymptomatic intestinal infections, colitis and extraintestinal infections.

Metronidazole is the drug of choice for the treatment of intestinal infections (except for the asymptomatic ones) and all the other infections for which Entamoeba histolytica has to be blamed.
Although the drug doesn't remove cysts and a luminal agent, such as Iodoquinol, has to be added to the regimen to completely get rid off the infection, metronidazole is nicely active against trophozoites.

The nitro group, in fact, is reduced by the protozoan itself, resulting in activation of the drug (although this has not been completely comfirmed yet).

Trichomoniasis is generally treated with metronidazole too, although resistance has been reported.

The reason why I chose this molecule, however, is because of its side effects. Among the most common ones, a metallic taste in your mouth makes it not the best to go with your Thanksgiving turkey (or anything else).

Eerie dark urines may appear, as well as insomnia, vertigo, weakness and paresthesias.
More rarely, people taking metronidazole are subject to severe central nervous system toxicity (including seizures)

More interestingly, metronidazole has disulfiram-like effect: so, you'd better stop drinking while you're taking it, unless you like vomiting very much...

For the grand finale, if you suffer from bipolar disorder and take lithium, its toxicity might be dramatically increased by metronidazole.

Going home at 6pm, riding a bicycle under heavy rain, listening to the Interpol and thinking about what your pharmaceutical chemistry professor has just explained. Which is that the reason why physostigmine is unstable at low pH, as proved, lies in the carbon I circled, which is actually, believe it or not, a modified carbonyl.

This is not that mad if you can see (and I'm sure you can) the close resemblance to a ketal.

Can you think of anything better?

Tonight, however, we've managed to restore the normal service and here we are, talking about a well-known class of drugs: tetracyclines.



Basically, they are broad-spectrum antibiotic with bacteriostatic activity against anaerobes, rickettsiae, chlamydiae and mycoplasmas, above all. In clinical use, tetracyclines are prescribed in the treatment of infections with Mycoplasma pneumoniae, in combined regimens to wipe out Helicobacter pylori and in some unpleasant sexually transmitted diseases. Besides, they can be used to cure community-acquired pneumonia, acne and leptospirosis.

Tetracyclines bind to the 30S subunit, which is present in bacteria only, leaving human ribosomes (and, consequently, our protein synthesis) unaltered. By the way, our mighty tetracycline blocks the aminoacyl-tRNA, which, in a nutshell, can't bind to m-RNA any more.
Sure, there is resistance. In particular, bacteria can produce an efflux pump, whose genes are encoded on a horizontally transmittable plasmid.

Looking at the basic structure, you'll easily recognise the chelating potential of the molecule. Such a reactivity means there are many interactions with food: milk, for instance, due to calcium ions, impairs the absorption of these drugs.
On the other hand, tetracyclines cause huge issues, especially in babies, reacting with calcium deposited in bones and teeth (they can even produce a pretty eerie fluorescence).

Other intersting drawbacks include a modification of normal intestinal flora: so, candidiasis and enterocolitis could be a consequence, because the physiological balance of intestinal bacteria is dramatically altered.
Another phenomenon I'd like to highlight is photosensitization (quite common, especially if, like me, you're skin is fair) and nitrogen retention, due to their moderate kidney toxicity.

Good evening and welcome! Chemical Forums supremo Mitch recently defined this blog as full of "hard-core pharmaceutical" stuff. I must say I really like this definition.
I have liked it so much that, tonight, I've got something even more radical for you. Tonight, SNS gets INSANE! Frankly, I can't find a better way to describe this synthesis of an already genuinely insane drug: Atracurium

Yes, another curare-like substance, a non-depolarising neuromuscular blocker used in hospitals to relax skeletal muscles.

I said this is insane because the drug was designed to look like an outrageous poison such as curare and because this (total) synthesis starts from a simple substance your grandma may use to prepare sweet cakes and other highly gratifying stuff: vanillin.
We therefore turn it into a derivative of less-likely-to-be-found-at-grandma's-house papaverine: tetrahydropapaverine. Oh, well, it depends on your grandparents, of course...

So, let's put an end to this talking: it's time to drown into madness.



The first steps are common and quite boring, although, as my professor kindly pointed out, you'd better make sure you don't have acid in your mixture when adding KCN.

The solution of cyanide is separated in two groups (no idea about the ratio): the former undergoes hydrogenation, whereas the latter is put in an aqueous solution of sulphuric acid. Neither HCl nor nitric acid: frankly, I inferred the reason is because my professor doesn't like them. Oh, well, he said HCl may hydrolyze the ether, even if diluted, and nitric acid is annoyingly photosensitive...
Then, the acid is converted into the more reactive acyl chloride and reacts with the amine.

Here comes the tricky part: phosphoric trichloride acts as a Lewis acid (yes, I said acid, not base) and as a dehydrator. Phosphorus activates the carbon and, in my opinion, the tertiary hydroxyl facilitates the following dehydration.

What I labelled an insane reactant is yielded by a reaction between two equivalents of but-2-enoyl chloride and one of pentandiol.

That's it: we methylate and here is our final, outrageous, insane product.