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248 12 Enzymatic inhibition: other antibacterial agents
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the best known tetracyclines is chlortetracycline (Aureomycin®) (Fig. 12.8), which was
discovered in 1948. It is a broad-spectrum antibiotic active against gram-positive and
gram-negative bacteria. It unfortunately kills the intestinal flora that is responsible
for the preparat ion of vitamin K, a vitamin necessary for the coagulation process.
There are three main types of vitamin K: K1 is the most efficient of the three and is
found in abundance in fruits and vegetables. Vitamin K2, on the other hand, is of animal origin and is synthesized within the human organism itself by intestinal bacteria.
Vitamin K3 is a synthetic variety of vitamin K, developed in the laboratory, and whose
use is recommended only under medical prescription.
Fig. 12.8: Aureomycin®as an example of a tetracycline.
12.9.4 Chloramphenicol
Chloramphenicol is an antibiotic that was obtained for the first time from a soil bacterium of actinomycetales, Streptomyces venezuelae. It is currently produced by synthesis. It has two stereocenters, but only the R,R isomer is the active form (Fig. 12.9).
Fig. 12.9: Chloramphenicol.
Chloramphenicol binds to the 50S subunit of ribosomes and appears to act by inhibiting the movement of ribosomes along the mRNA, probably by inhibition of the peptidyl transferase reaction, by which the peptide chain is increased. Chloramphenicol,
a drug effective against a broad spectrum of microorganisms, especially staphylococci, is limited to very serious infections such as typhoid fever, due to its serious side
effects (bone marrow damage including aplastic anemia) in humans.
12.9.4.1 Aldol reaction
The aldol reaction (aldol addition) is a reaction that combines two carbonyl compounds
(aldehydes or ketones) to form a new β-hydroxy carbonyl compound (Scheme 12.8).
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Scheme 12.8: Aldol reaction.
12.9.4.2 Nitro-aldol reaction or the Henry reaction
The Henry reaction (also referred to as the nitro-aldol reaction) is a classic
carbon–carbon bond formation reaction in organic chemistry. Discovered in 1895
by the Belgian chemist Louis Henry (1834– 1913), it is the combination of a nitroal-
Scheme 12.9: Henry reaction.
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kane and an aldehyde or ketone in the presence of a base to form β-nitro alcohols
(Scheme 12.9). This type of reaction is commonly referred to as a “nitro-aldol” reaction (nitroalkane, aldehyde, and alcohol). It is nearly analogous to the aldol reaction that had been discovered 23 years prior.
The synthesis of chloramphenicol begins with the aldol condensation of the benzaldehyde with 2-nitroethanol to give a mixture of the four enantiomers of the nitropropanediol, which are catalytically reduced to aminodiols. threo isomer is crystallized out
and resolved as a diastereomeric salt to give the enantiomer of the desired
configuration. Further acylation with dichloroacetyl chloride, followed by protection of
the hydroxyl groups with acetic anhydride, allows nitration of the aromatic ring. Finally, saponification leads to the active enantiomer (Scheme 12.10).
12.9.5 Erythromycin
Erythromycin, an antibiotic belonging to the macrolide family, is very effective against
infections produced by gram-positive cocci (Fig. 12.10). It is used to treat various bacterial infections of the respiratory tract, urinary tract, ear and skin infections, gonorrhea,
syphilis, rheumatic fever, whooping cough, and diphtheria.
It acts by interfering with the production of proteins that bacteria need to multiply, thus halting the growth of bacteria and the spread of infection. Erythromycin has
an antibacterial activity very similar to penicillins and is used as an antibiotic alternative in patients who are allergic to penicillins. It may have a bactericidal or bacteriostatic action, depending on the microorganism and the concentration of the drug. It
interferes with the formation of essential proteins in the invasive bacteria, which prevents their multiplication and growth.
D-(–)-threo
12.9.6 Aminoacridines
Aminoacridridines, such as proflavin, are topical antibacterial agents used during
World War II for the treatment of superficial wounds. Pro flavin is intercalated between the double DNA helix, inhibiting transcription and replication (Fig. 12.11).
Acridine is a flat, weakly basic molecule, but when the amino group is substituted
at positions 3, 6, or 9, strong bases are obtained as a result of the resonance that delocalizes the positive charge of cation 12.1 (Scheme 12.11).
Albert’s studies in 1939, involving a considerable number of acridine derivatives
and various species of bacteria, revealed that only those capable of high ionization at
physiological pH were active as antibacterial drugs. Consequently, proflavin (3,6diaminoacridine) and 9-aminoacridine were widely used as antiseptics.
A second clue about the mode of action of the aminoacridines was provided by
the discovery that a minimal area of planarity for antibacterial activity was essential.
Scheme 12.10: Synthesis of chloramphenicol.
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12.9 Antibacterial agents affecting protein synthesis 251
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Fig. 12.10: Erythromycin.
Fig. 12.11: Intercalation of proflavin in DNA.
When compounds 12.2 and 12.3 (Fig. 12.12), representing successive removal of one or
two benzene rings from aminoacridine, were examined, antibacterial activity was
lost even when high ionization, that is, significance of ionic resonance hybrids, was
maintained:
The loss of antibacterial activity on decreasing the planar surface was reaffirmed
by the reduced activity of 1,2,3,4-tetrahydro-9-acridine. The acridine flat ring is intercalated in the DNA due to the following two factors:
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Scheme 12.11: Resonance forms of the 9-aminoacridinium cation.
Fig. 12.12: 4-Aminoquinoline (12.2) and 4-aminopyridine (12.3).
(a) By the van der Waals forces that are established between the purine (e.g., ade-
nine) and pyrimidine rings (e.g., thymine) since acridine is a π-electron deficient
system, whereas both adenine and thymine are π-electron excessive systems. A
charge-transfer complex can therefore be established between the two types of
heterocyclic aromatic systems
(b) In addition, the acridine ring thus binding in this way is in the ideal arrangement
for its two positively charged nitrogen atoms to establish ionic interactions with
two phosphate groups of the double-stranded DNA structure
The interaction of proflavin with DNA increases the viscosity coefficient and decreases the sedimentation coefficient of the complex in solution. These changes are
attributed among others to increased stiffness of the double helix. X-ray studies indicate that an aminoacridine molecule stacks parallel to base pairs in a 1:3 ratio.
12.9.7 1,8-Naphthyridine and fluoroquinolones
Quinolones and fluoroquinolones are modern drugs within the antibacterial therapeutic arsenal (Fig. 12.13). They are particularly interesting for the treatment of both urinary tract infections and infections that are resistant to classical antibacterial agents.
Nalidixic acid is active against gram-negative bacteria and is useful as a therapeutic agent against infections of the urinary tract. It can be administered orally, but bacteria can develop resistance.
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Fig. 12.13: 1,8-Naphthyridine and fluoroquinolones.
A great advancement was achieved when a fluorine atom at position 6 and a piperazino moiety at position 7 of the heteroaromatic skeleton were introduced. These modifications led to enoxacin, structurally related to nalidixic acid, and to norfloxacin
(quinolone antibiotic), which has high activity against gram-negative and grampositive bacteria. It is also active against the highly resistant P. aeruginosa.
An extra mo dification led to ciprofloxacin, which is considered the most widely
available antibacterial agent on the market. They are the only antibacterial agents
that exert their bactericidal activity by binding to bacterial topoisomerases and inhibiting them, although this would not be the only mechanism of action. Topoisomerases
are enzymes that control the supercoiling and unwinding of bacterial DNA. Supercoiling allows the long molecule of DNA to pack inside a bacterial cell. This structure
must be unwound to allow different functions such as replication, transcription, and
DNA repair. Inhibiting the activity of these enzymes prevents the bacterial cell from
producing the proteins necessary for its repair, growth, and reproduction. Prolonged
inhibition would thus lead to the death of the cell. There are four types of topoisomerases. The quinolones can act on DNA-gyrase (also called topoisomerase type II) and
topoisomerase type IV. They do not act on topoisomerases I and III.
12.9.7.1 Orthoester
An orthoester is a functional group containing three alkoxy groups attached to one
carbon atom, that is, with the general formula RC(OR′)
ered as products of exhaustive alkylation of unstable orthocarboxylic acids and it is
from these that the name “orthoester” is derived. An example is triethyl orthoacetate,
C(OCH2CH3)3, more correctly known as 1,1,1-triethoxyethane.
CH
3
Orthoesters can be prepared by the Pinner reaction, in which nitriles react with
alcohol s in the presence of o ne equivalent of hydrogen chloride (Scheme 12.12). The
reaction proceeds by the formation of imidoester or iminoether hydrochloride.
Upon standing in the presence of excess alcohol, this intermediate converts to the
orthoester.
. Orthoesters may be consid-
3
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Scheme 12.12: Orthoesters.
12.9.7.2 Synthesis of diethyl ethoxymethylenemalonate, intermediate for
the preparation of norfloxacin and nalidixic acid
Diethyl malonate is used in the preparation of several medicinally useful compounds,
including norfloxacin and nalidixic acid, through the formation of diethyl ethoxymethylenemalonate (Scheme 12.13).
Scheme 12.13: Preparation of diethyl ethoxymethylenemalonate.
Norfloxacin is obtained by condensation of 4-fluoro-3-chloroaniline and diethyl 2ethoxymethylenemalonate with elimination of ethanol, followed by heating in a highboiling point solvent such as diphenyl ether, to give the quinolone. Subsequently the
nitrogen is alkylated, the ester saponified, and the chlorine replaced by the piperazine
ring to give the desired product. This reaction is possible because the chlorine atom is
para with respect to an electron-withdrawing carbonyl group (Scheme 12.14).
Nalidixic acid is synthesized by a similar route, but starting from 2-amino-6methylpyridine. In this case, the benzene ring of norfloxacin has been replaced by
its isostere pyridine (Scheme 12.15).
The synthesis of ciprofloxacin is outlined in Scheme 12.16. Bayer synthesis of ciprofloxacin uses 2,4-dichloro-5-fluorobenzoyl chloride (12.4) as the starting material. With
the aid of magnesium ethoxide, condensation of the acid chloride 12.4 with diethyl mal-
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Scheme 12.14: Synthesis of norfloxacin.
Scheme 12.15: Synthesis of nalidixic acid.
onate yields ketone 12.5, which is then decarboxylated using p-toluenesulfonic acid to
form ethyl 2,4-dichloro-5-fluorobenzoylacetate (12.6).
A Dieckman-type condensation of 12.6 with the ethyl orthoformate is carried out in
acetic anhydride, which refluxes to yield the ethyl acrylate 12.7.When12.7 is treated
with cyclopropylamine in ethanol, an Michael addition is produced, followed by the
subsequent expulsion of the ethoxy group to give enamine 12.8 with the stereochemistry shown in Scheme 12.16. Under the influence of a base such as K
12.8 then undergoes an intramolecular S
the ethyl ester group of 12.9 is carried out using a catalytic amount of concentrated sulfuric acid in a 1:1 mixture of acetic acid/H
takes place between 12.10 and piperazine to give ciprofloxacin. Chemoselectivity is the
result of the “activating” effect of the carbonyl group at para-position (Scheme 12.16).
,NaH,orKH,
2CO3
Ar to produce quinolone 12.9. Hydrolysis of
N
O. Finally, a chemioselective SNAr reaction
2
12.10 Why 4-quinolone-3-carboxylic acids do not decarboxylate despite being β-ketoacids? 257
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Scheme 12.16: Synthesis of ciprofloxacin.
12.10 Why 4-quinolone-3-carboxylic acids do not decarboxylate
despite being β-ketoacids?
A β-keto acid is a carboxylic acid containing a carbonyl group two bonds away from
the carboxyl group. β-keto acids undergo thermal decarboxylation (lose carbon dioxide) quite easily because the immediate product of decarboxylation will be a resonance
stabilized enolate anion. Tautomerism of the enolate leads to a ketone. Scheme 12.17
gives a possible explanation for the existence of 4-hydroxy-3-carboxyquinolinium salt,
as a consequence of the gain in stability resulting from the aromaticity of the quinolinium system.
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