[Reissue under better title]

Due to a recent hospital stay with pneumonia, I found myself staggeringly bored. To stave off some of this I began to look into an antibiotic I was given that I had never heard of- Levofloxacin. The structure of this antibiotic was different from antibiotics I was previously familiar with. Natural I suppose, considering that I’ve been immersed in organo-transition metal chemistry for most of my industrial career. Metal-carbon bonds are quite useful in some sectors but not as drugs.

Levofloxacin is a good place to go deep diving into some of the murkier depths of chemical nomenclature. The complicated-looking chemical naming system exists to unambiguously represent the composition and shape of molecules. Certain features and properties of a molecule confer important attributes that need categorizing, thus requiring descriptive names rather than just a number. Every different chemical substance is, well, different and their chemical names must reveal a unique identity. Two or more substances with the same name leads to nothing but trouble.

Chemical substances can be grouped into categories to associate them with related aspects. We have noble gases, transition metals, hydrocarbons, pnictogens, polymers, acids, and bases etc. But the categories allow for variation when particular attributes are under discussion.

The names of chemical substances can be very off-putting to non-chemists and often does lead them to abandon their search for information. A few have even suggested that if you cannot pronounce the name it must be bad. Even worse than the polysyllabic and numbered character strings are the various synonyms. Consider simple toluene which is actually not so bad-

In chemical nomenclature there is just a bit of flexibility in how numbers, syllables and name fragments can be assembled as the toluene example above shows, if you don’t read the rules too closely. The plethora of names come from historical trade names or long-time industrial use or may just predate systematic nomenclature now in use. There is also the German Beilstein and Gmelin organic and inorganic nomenclature as well, but these seem to be outdated.

As always, a proper chemical name describes the composition and 3-dimensional connectivity of the chemical structure of a molecule. These names are commonly listed in one of the two dominant styles of chemical nomenclature in the world- International Union of Pure and Applied Chemists (IUPAC) and Chemical Abstracts Service (CAS). IUPAC tends to be taught in undergraduate chemistry because it always has been and is maybe a trifle easier.

The CAS databases contain more than 200 million organic and inorganic chemical substances and about 70 million protein and nucleic acid sequences. There are two search platforms available in CAS- SciFinder and STN. STN is much more cryptic and harder to learn than SciFinder. Some say there are weaknesses in patent searching in SciFinder alone. For IP work I use SciFinder, Google Patents and the USPTO in combination. All three offer different kinds of searching capability.

Levofloxacin is a biocidal antibiotic effective against both gram-positive and gram-negative bacteria. It is an inhibitor of both DNA gyrase and topoisomerase IV enzymes which are involved in shaping the geometry of bacterial plasmids, or rings of bacterial DNA. Plasmids have to fit inside the bacterial cell wall and those that are not made compact enough are too long to allow successful formation of daughter cells in reproduction resulting in cell death. Other kinds of antibiotics are bacteriostatic and often work better in one or the other of Gram-Negative or Gram-Positive bacteria. Gram stains are effective with certain types of bacterial cell walls and not with others. The ability of a dye to stain a colony of bacteria a particular way is used to help identify bacteria.

Consider the name of Levofloxacin from IUPAC: (-)-(S)-9-fluoro-2,3-dihydro-3-methyl-10-(4-methyl-1-piperazinyl)-7-oxo-7H-pyrido[1,2,3-de]-1,4-benzoxazine-6-carboxylic acid hemihydrate. The name is a string of characters with numbers indicating attachment points. The core of the structure is a 1,4-benzoxazine ring system which is festooned with a carboxylic acid and a few other groups. The core structure was identified and numbered previously by someone according to rules. The IUPAC name also specifies that it is a hemihydrate, meaning that there is one molecule of water associated with every two (hemi) molecules of Levofloxacin. For some reason the CAS name does not include the hemihydrate in the name, probably because it was not mentioned in the composition when registered with CAS. How it is in the IUPAC name is not known to me.

More pain. The IUPAC name above indicates “(-)-(S)-“. Molecules with “handedness” are said to be chiral and are not superimposable with their mirror images, similar to a right-hand being shape-incompatible with a left glove. These molecules can be prepared as individuals of single handedness or all of the way to a 50:50 mixture of left and right-handed. A 50:50 mixture of left and right-handed is called a “racemate” (RASS eh mate). Each handedness version is a type of isomer called an “enantiomer“. A substance consisting of a pure enantiomer is said to be “enantiomerically pure.”

Isolated enantiomers have the ability to rotate plane polarized light as measured by a polarimeter. Plane polarized light is a light beam where the electric field vectors of the electromagnetic radiation are all vibrating in a single plane. Obviously the magnetic vectors are polarized as well, but it is the electric field that is usually mentioned. The angle of the oscillating ray’s electric fields along the axis can be tilted one way or the other depending on the interaction with matter. Reflected light and skyglow are polarized as well. Molecules with handedness rotate the vibrational plane and by an angle dependent on the light frequency and the amount of chiral mass traveled through. Light that is rotated counterclockwise, or levorotary, has a (-) sign and signified with an “l” and light that is rotated clockwise is dextrorotary and has a (+) sign and signified with a “d.” If a molecule rotates plane polarized light, the substance is said to be “optically active.” The amount of rotation is dependent on the light frequency, frequently the sodium D line (actually a close doublet) which is often used as the standard source for this. Mercury lines, e.g., 354 nm, can be used if the D line results in a low measured rotation. Substances that do not rotate plane polarized light are often designated “dl” as an abbreviation for racemic.

D-Glucose, or dextrose, solutions rotate plane polarized light in the clockwise, dextrorotary direction, thus the “D” in the name.

Commercial L-lactic acid derived from fermentation is “L” for levorotary. This enantiomerically enriched lactic acid is used to make the lactide monomer for poly(lactic acid), PLA. Only the lactide dimer from L-lactic acid gives the desired PLA isomer. The racemic form of lactic acid is not useful for PLA due to undesirable physical properties in the polymer.

A ratio can be taken from an experimental sample that may range from 50:50 racemate to 100 % of a single enantiomer to give the optical purity of the chiral material, representing the proportion of pure enantiomer. Often the measure % ee, or percent enantiomeric excess is used to describe enantiomeric purity. A 95:5 mixture of enantiomers would have a 90 % excess enantiomeric of one enantiomer. Chemical synthesis of 99 % ee can be quite difficult.

A racemate does not have a net rotation of plane polarized light. The (-) sign represents the “levo” part of the levofloxacin, referring to counterclockwise rotation of plane polarized light. Prior to the appearance of reliable analytical methods for the determination of enantiomeric purity, polarimetry and optical rotation were the method of choice. Today, Gas Chromatography (GC) and High Performance Liquid Chromatography (HPLC) columns and chiral shift reagents for ¹H-NMR that can provide baseline separation of enantiomers.

The (S) character in the name indicates the handedness of a molecule as determined by standard selection rules defined by an organization for assigning absolute configuration. “S” stands for the Latin word “sinister” meaning left-handed. There is no simple calculation to go between absolute configuration and sign. The (-) sign can indicate which particular enantiomer is under consideration with an easy measurement if it has been previously correlated. (-)-(R) and (+)-(S) enantiomers can and do occur. The “(S)” defines only the precise configuration of atoms about an asymmetrically situated atom in a molecule based on a few simple rules. The mirror image of (-)-(S)- would be (+)-(R)-, “R” for rectus meaning right-handed in Latin.

The first task in assigning a name to a molecule is to determine the “core” structure. This is the basis of the name. Your molecule will be a variety of “the core structure.” This is not so easy because IUPAC or CAS will have already done this and your choice may or may not match. Referring to the CAS name below, you can see that some structural fragments end in “-yl,” “-ic” or “-o”. These signal that the fragments are not the core structure, they are attachments. The core structure onto which everything else is attached is the “1,4-benzoxazine”. It is a standalone chemical name which may be modified. This is a very obscure fact that most won’t know, but the “-ine” suffix indicates that the core structure is an amine, full stop. Other nitrogen indicators like azo, aza, amino, ammonium, nitro, azido, etc, suggest a nitrogen group attachment to something else.

Does it help to have a college degree in chemistry to know this stuff? Sorry but yes. In the set of all worldly knowledge, this is pretty obscure.

The CAS name for levofloxacin is 7H-Pyrido[1,2,3-de]-1,4-benzoxazine-6-carboxylic acid, 9-fluoro-2,3-dihydro-3-methyl-10-(4-methyl-1-piperazinyl)-7-oxo-, (3S)-. The core structure seems to be the 1,4-benzoxazine. CAS has a ring-system handbook that defines and numbers all of the known ring systems. The significance of CAS is that they assign and maintains the official CAS registry number, CASRN, which is depended upon world-wide for the exact composition and connectivity and geometry of substances. There is a very extensive rule book that rigidly defines a chemical name with rooms of CAS experts sitting in a building in Columbus, OH, to assign these names. For levofloxacin the CASRN is 100986-85-4. Today, CASRNs are usually directly searchable on Google. The final digit “4” is a check digit for error entry detection.

Yet more pain. The more formal official CAS name, however, does not indicate the direction of rotation of plane polarized light. I suppose this is considered experimental data not needed in the name. The CAS nomenclature only shows “(3S)-” in the name, indicating the absolute “S” configuration at position 3 of the molecule. The business of handedness or shape in 3-space of a molecule is called “stereochemistry” and arises in several ways. The rules for assigning the absolute configurations of R or S enantiomers may depend on the features of the molecule.

This business of molecular handedness is mostly an issue for biochemistry and pharmaceuticals. A great many- most?- biomolecules have handedness themselves and are therefore subject to interactions with other biomolecules or drugs that depend on the precise shapes for their interactions. This is very important for the interaction between molecules like an enzyme and substrate or ligand.

In the absence of other chiral molecules, two enantiomers will have the same chemical properties when individually pure. However, a racemate consists of a pair of enantiomers. The interactions between R and R or S and S enantiomers, will be different than the interactions between a racemic mixture of R and S or S and R enantiomers. If there is more than one chiral feature in a molecule- say two- then the molecule could be R, R or R, S, or S, S, or S, R. This gives two pairs of enantiomers, each called a “diastereomer.” For instance, one substance with R, S and another with R,R will be substances chemically and physically different called diastereomers. The presence of a diastereomer in an enantiomeric drug product would likely be deemed a contaminant and removed.

A druggable disease-state is one that can be positively influenced by a drug molecule. This commonly involves the drug molecule docking with an enzyme to activate it or deactivate it. These enzymes are very large diastereomers having many chiral atoms giving them complex shapes that can result if the formation of a pocket in the protein structure called the “active site.” This active site has very particular shape and charge features provided by the chiral amino acid chain of the protein. An active site will have a shape that is compatible with the close fitting of a drug or other molecule similar to a hand in a glove. Many of these active sites bind the shape and charge of one enantiomer of a drug molecule more effectively than the other for a better fit. The drug, or substrate, may just sit there and block the action of an enzyme, shutting it down or activate it continuously. Other active sites may bind a drug and change the shape of the enzyme causing the enzyme to speed up or slow down for a throttling or accelerating effect elsewhere on the enzyme. This is called the allosteric effect.

So, you may be asking- big deal, what does it matter? In the world of pharmaceuticals, many drug substances can exist as single enantiomers, racemates or diastereomers. Racemates may be easiest to manufacture, but very often one of the enantiomers is more biologically active than the other. In fact, one enantiomer may be disastrously harmful. The classic example is Thalidomide. The S form caused birth defects and the R form did not. Pure R enantiomer was safe from teratogenicity but a racemic mixture of R and S was not.

Conclusion. A superficial look at a chemical name opens up insights into the chemical nature of a substance. What makes each chemical substance unique is their distribution of charge in 3-dimensions. The distribution is affected by the types of the atoms present, geometric features of the 3-dimensional shape and the ability of the system to allow charge to accumulate in particular places of the molecule. These attributes mentioned also set up the type and vigor of reactivity the molecule will display.