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172 Pharmaceutical Chemistry
7.11 RIFAMPICIN (RIFAMPIN)
It is a bactericidal macrolide antibiotic polyketide
drug that belongs to the rifamycin group. It is a
semisynthetic compound derived from
Amycolatopsis rifamycinica (formerly known as A.
mediterranei and Streptomyces mediterranei). It is
used in many antibiotic combination therapies
including tuberculosis, leprosy and Legionnaire’s
disease.
Prof. Piero Sensi and Dr. Maria Teresa Timbal
a research group from Lepetit Pharmaceuticals
research lab in Milan, Italy analysed a soil sample from pine forest on the French Riviera
and discovered a new bacterium with an antibiotic activity in 1957. This research group
was particularly fond of the French crime story Rififi, thus they decided to call these
compounds “rifamycins”. Later in 1959, it was named “rifampicin”.
It is used in the treatment of a number of bacteria and is best known for activity against
Mycobacterium strains, such as cause tuberculosis and Hansen’s disease. It can be used as
monotherapy for a few days as prophylaxis against meningitis, but resistance develops
quickly during the long treatment of active infections, so the drug is always used against
active infections in combination with other antibiotics.
HO
MeOCO OH
MeO
O
O
Rifampicin
NH
O
N
N
N
OHOH
OH
O
7.11.1 Specification
Name : Rifampicin
Molecular formula : C
43H58N4O12
Molecular weight : 823 g/mol
Melting point : 188-194°C
Physical state : Solid, reddish-orange powder
Solubility : Soluble in water, methanol, chloroform, ethyl acetate, DMSO, DMF,
THF.
7.11.2 Mode of Action
It inhibits DNA-dependent RNA polymerase in bacterial cells by binding its E-subunit,
thus preventing transcription to RNA and subsequent translation to proteins. Its lipophilic
nature makes it a good candidate to treat the meningitis form of tuberculosis, which
requires distribution to the central nervous system and penetration through the bloodbrain barrier.
5LIDPSLFLQUHVLVWDQWEDFWHULDSURGXFH51$SRO\PHUDVHVZLWKVXEWO\GLIIHUHQWǃVXEXQLW
structures which are not readily inhibited by the drug. In molecular biology research,
plasmids containing rifampicin-resistant genes are often used for colony screening.
Anti-Leprosy Drugs 173
7.11.3 Metabolism of Rifampicin
The drug is metabolised into compounds such as 25-desacetyl rifampicin, rifampicin
quinine, desacetyl rifampicin quinine, 3-formyl rifampicin SV, 3-formyl desacetyl
rifampicin, etc. These metabolites are eliminated easily from the system through the bile
and also the urine. The major metabolite, 25-desacetyl rifampicin, has been shown to be
active against M. tuberculosis as rifampicin itself. The quantity of rifampicin and three of its
metabolites 25-desacetyl rifampicin, 3-formyl rifampicin SV and 3-formyl desacetyl
rifampicin recovered in the urine has been found to increase from 3% of dose after oral
administration of 150 mg to approximately 12% after a 600 mg dose.
7.11.4 Absorption, Distribution and Excretion
It undergoes rapid and complete absorption after oral administration and best absorbed
with the empty stomach. Food may decrease the rate of absorption. It is easily absorbed
from the gastrointestinal tract. It is distributed into most body tissues and fluids, including
the cerebrospinal fluid and has property of intracellular penetration. Oral administration
of this drug results in peak plasma concentrations in about 2–4 hours. The half-life of
rifampicin ranges from 1.5 to 5 hours, though hepatic impairment will significantly increase
it. It crosses the placenta and also binds with protein about 80%. It is extensively eliminated
by intestinal and hepatic metabolism. Only about 7% of the administered drug will be
excreted unchanged through the urine, though urinary elimination accounts for about
only 30% of the dose of the drug that is excreted. About 60% to 65% is excreted through
the faeces. The drug and its metabolites are largely excreted in bile and eliminated in
stools. This drug undergoes enterohepatic recirculation as does its metabolites. Only a
small portion of the dose is excreted unchanged in the urine (15–25%), giving the urine an
orange colour.
It is associated with numerous drug interactions, thus it acts as a potent enzyme inducer
of the cytochrome P450 (viz., CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP3A4,
CYP3A5 and CYP3A7) oxidase system. It also has an inducer effect on its own hepatic
metabolism; thus repeated administration of rifampicin increases its oral clearance by
inducing its own gut and hepatic metabolism or enhancing its biliary excretion. It also
induces the activity of the glucuronyltransferases, sulphotransferases and the efflux
transporter P-glycoprotein.
7.11.5 Side Effects
Hepatotoxicity (jaundice, hepatitis and liver failure) is a major side effect of this drug. The
common unwanted effects include fever, gastrointestinal disturbances, rashes, immunological reactions, rash, redness and watering of eyes, nausea, vomiting, abdominal cramps
with or without diarrhoea, chills, fever, headache, arthralgia and malaise.
174 Pharmaceutical Chemistry
7.12 CLARITHROMYCIN
It is a macrolide antibiotic used for treatment of various
O
diseases, viz., pharyngitis, tonsillitis, acute maxillary sinusitis,
acute bacterial exacerbation of chronic bronchitis, pneumonia
(especially atypical pneumonias associated with Chlamydia
pneumoniae), skin infections, etc. It is a semisynthetic macrolide
antibiotic derived from erythromycin that is active against a
variety of microorganisms.
7.12.1 Specification
Name : Clarithromycin (Biaxin)
Molecular formula : C
38H69NO13
HO
O
O O
Clarithromycin
OH
OMe
HO
O
O
O
OMe
NMe
OH
2
Molecular weight : 748 g/mol
Melting point : 220°C
Physical state : Solid, colourless needles
Solubility : Soluble in water and polar solvents.
7.12.2 Mode of Action
It interferes in the synthesis of protein and thus it may prevent bacteria from further
development. It binds to the subunit 50S of the bacterial ribosome and thus inhibits the
translocation of aminoacyl tRNA and prevents peptide chain elongation. The antimicrobial
spectrum of clarithromycin is similar to erythromycin but is more effective against certain
Gram-negative bacteria (Legionella pneumophila). Besides this, it is also effective on certain
strains, (viz., Haemophilus influenzae, Streptococcus pneumoniae and Neisseria gonorrhoeae).
7.12.3 Metabolism of Clarithromycin
Clarithromycin is extensively metabolized in the liver, principally by oxidative Ndemethylation and hydroxylation and forms two metabolites; the major and active
metabolite is 14-hydroxyclarithromycin in serum and with substantial antibacterial activity
(especially R isomer) and inactive metabolite N-desmethylclarithromycin. It has a fairly
rapid first-pass hepatic metabolism. However, 14-hydroxy clarithromycin metabolite is
almost twice as active and has a half life of 7 hours compared to clarithromycin’s.
Clarithromycin and its metabolites are eliminated through urinary and biliary excretion.
Its elimination half-life is about 3 to 4 hours.
7.12.4 Adsorption, Distribution and Excretion
It is acid-stable and can be taken orally. It is readily absorbed, and diffused into most
tissues and phagocytes in high concentration. High concentration of clarithromycin in the
tissues leads to more effective and actively transportation to the site of infection. During
active phagocytosis, large concentrations of clarithromycin are released. The concentration
of this drug in the tissues can be over ten times higher than in plasma. Highest concentrations
are found in the liver and lung tissues. Clarithromycin and its metabolites are eliminated
through urinary and biliary excretion.
Anti-Leprosy Drugs 175
7.12.5 Side Effects
Most common side effects are gastrointestinal (abdominal pain, nausea, diarrhoea, extreme
irritability, vomiting, facial swelling) and headaches, dizziness, rashes, alteration in senses
of smell and taste, jaundice, renal failure, chest pain, shortness of breath, etc.
7.13 MINOCYCLINE
It is a unnaturally occurring broad-spectrum tetracycline
bacteriostatic antibiotic which has a broader spectrum
than the other members of the group. It has very long
half-life and generally has serum levels 2–4 times that of
the simple water soluble tetracyclines.
In 1972, Lederle Laboratories synthesized minocyclin
OH O OH O
N
OH
Minocycline
O
NH
2
OH
N
.HCl
from the natural tetracycline antibiotics.
7.13.1 Specification
Name : 4,7-Bis(dimethylamino)-1,4,4a,5,5a,6,11,12a-octahydro-3,10,12,12a-
tetrahydroxy-1,11-dioxo-2-naphthacene-carboxamidemonohydrochloride
Molecular formula : C
23H27N3O7
+&O
Molecular weight : 493.94 g/mol
Physical state : Solid bright yellow-orange
Solubility : Soluble in polar solvents
7.13.2 Synthesis of Minocycline
Synthesis of minocycline using 9-Nitro isomer
O
OH
NH
OH
2
O
OH
N
t-BuONO
H2SO
O
OH
4
NH
2
OH O
H
2
PtO
2
OH
OH
O
OH
N
OH O OH O
H2N
O
OH
NH
2
H
2
Pd/C
OH
O2N
OH O
O
OH
N
NH
OH
O
O
OH
N
HNO
2
H2SO
H2N
3
4
NH
OH
KNO
3
2
HF
OH O OH
NO
2
OH O
O
OH
N
OH
O OH O
N
2
NO
2
OH
O
OH
N
i) aq. HCHO, H2/Pd-C
O
ii) H
NH
2
2
OH O OH O
N
OH
Minocycline
O
NH
2
OH
N
176 Pharmaceutical Chemistry
7.13.3 Mode of Action
This drug is bacteriostatic and the mechanism of action is similar to tetracyclines which act
through inhibiting protein synthesis by reversibly binding to 30S ribosomal subunits of
susceptible organisms, thereby preventing binding to those ribosomes of aminoacyl
t-RNA. Tetracyclines are also believed to reversibly bind to 50S ribosomes and additionally
alter cytoplasmic membrane permeability in susceptible organisms. In high concentrations,
tetracyclines can also inhibit protein synthesis by mammalian cells. This drug also has
antimicrobial effect by the inhibition of protein synthesis against a wide range of Grampositive (viz., Staphylococcus aureus, Streptococcus pneumonia, etc.), Gram-negative organisms
(viz., Escherichia coli, Haemophilus influenza, etc.) and other microorganisms, viz., Actinomyces
species, Clostridium species, Entamoeba species, etc.
7.13.4 Metabolites of Minocycline
The principal metabolite of Minocycline is 9-hydroxyminocycline which helps in simulating
an enzymatic oxygenase. Two other major metabolites are probably mono-N-demethylated
derivatives and a substantial amount of 4-epiminocycline, which probably resulted from
minocycline epimerization rather than biotransformation.
7.13.5 Absorption, Distribution and Excretion
It is well absorbed from the GI tract with peak serum levels observed within 2–4 hours.
Minocycline is highly lipid soluble and is distributed widely throughout the body. It is
approximately 70–80% bound to plasma proteins, exhibits a serum half-life of 11–18 hours.
Therapeutic levels can be found in the CSF (whether meninges are inflammed or not),
prostate, saliva and eye. It is extensively metabolized in the liver and primarily excreted
as inactive metabolites in the faeces and urine. Less than 20% is excreted unchanged in the
urine. The half-life in dogs is about 7 hours.
7.13.6 Side Effects
It may cause abdominal discomfort, diarrhoea, esophageal ulcers, nausea, vomiting,
anorexia, teeth demineralization, skeletal growth retardation, jaundice, hyperphosphatemia, red rash to blistering, hearing loss, visual disturbances, dizziness, drowsiness, and
headache.
7.14 OTHER SULFONE DERIVATIVES ACTIVE AGAINST LEPROSY
Other sulfone derivatives such as DADDS (4,4-Diacetyldiaminodiphenyl sulfone) (Fig.
7.5) are the most promising of the long acting sulfones in respect to activity in leprosy.
DADDS is probably metabolized into dapsone or the monoacetyl derivative is slowly
released in the tissue by deacetylating enzymes, and the observed activity of the drug
against M. leprae is due to circulating dapsone. Some related derivatives of chaulmoogra
Anti-Leprosy Drugs 177
oil, certain antibiotics, antimycobacterial agents have been studied for their activity in
human leprosy. In early 1940s short and long acting sulphonamides (A) were found to be
active in leprosy. They are active in both multibacillary and paucibacillary forms of leprosy.
O
O
DADDS
O
S
O
S
H
N
R
O
N
H
Sulfaphenazole
R =
N
O
N
H
N
N
OMe
NN
OMe
Sulfadimethoxine
OMe
OMe
A
NH
2
MeO
Sulfamethoxypyrazine
Fig. 7.5: Sulfone derivatives
N
N
N
OMe
Sulfamethoxypyridazine
NN
Sulfomethoxine
Methimazole (Tapazole), Nicotinamide with dapsone (effective against murine leprosy),
Vadrine, Neovadrine, aminosalicyalic acid derivatives (active against leprosy),
Pyrazinamide, Ethambutol, Ditophal, and Macrocyclon are the other major components
which are used in the treatment of leprosy (Fig. 7.6).
O
Nicotinamide
NH
2
O
N
Pyrazinamide
Fig. 7.6: Other components used in the treatment of leprosy
NH
2
O
O
N
Vadrine
NH
N
O
SEt
SEtO
Ditophal
OH
N
H
HO
Ethambutol
H
N
N
S
N
H
Methimazole
7.15 TREATMENT OF LEPROSY USING CHAULMOOGRA OIL
Chaulmoogra oil is extracted from the seeds of Hydnocarpus wightiana and also known as
Hydnocarpus oil. It has been used for treating leprosy and other skin diseases in India
since ancient times. Sir Leonard Rogers in 1916, introduced sodium hydnocarpate
(ALEPOL) for treatment of leprosy which was the beginning of leprosy control in India
after 18
Faget of the National Hansen’s Disease Center (renamed the Gillis W. Long Hansen’s
Disease Center in the 1980s) in Carville, Louisiana, showed remarkable benefits of Promin
in treating the disease. This discovery was heralded as “the miracle of Carville” and
marked the onset of the first real hope that leprosy could be successfully treated and cured.
th
century while modern era of leprosy treatment began in the 1940s, when Dr. Guy
178 Pharmaceutical Chemistry
Chaulmoogra oil is characterized by the presence of glycerides of cyclopentenyl fatty
acids (CFAs), hydnocarpic (48%), chaulmoogric (27%) and gorlic acids as major constituents
and small amount of glycerides of palmitic acid (6%) and oleic acid (12%). The cyclic acids
are formed during last 3-4 months of maturation of the fruits. The seeds of H. Wightiana
contain flavonolignan hydnocarpin, isohydnocarpin, methoxy hydnocarpin, apigenin,
lutcolin, chrysocriol, hydnowightin and cyclopentenoid cyanohydrins glycosides (Fig. 7.7).
The pharmacological evaluation of the seed and oil showed potential activity against M.
leprae and was effective in treating early cases of leprosy.
O
OH
Aleprolic acid
COOH COOH COOH
(H2C)
10
Hydnocarpic acid
Fig. 7.7: Structure of various fatty acids indentified in Chaulmoogra oils
COOH
(H2C)
4
Aleprestic acid
Chaulmoogric acid
(H2C)
(H2C)
6
Aleprylic acid
12
COOH
(H2C)
Alepric acid
(H2C)
22
Gorlic acid
COOH
8
7.16 WHO RECOMMENDED CHEMOTHERAPEUTIC REGIMENS
7.16.1 Multibacillary Leprosy
The WHO MDT regimen for multibacillary leprosy has been very successful and has been
widely implemended as recommended. Thus, it is recommended that all multibacillary
patients must be treated with the standard WHO regimen for 24 months, since it considered
that such a change was safe and would increase the use of the regimen under field
conditions. It is also recommended by scientists that there should be no changes in the
composition or doses of drugs or in the “rhythm” (i.e., frequency and pattern) of therapy.
For adults, the recommended standard regimen for multibacillary leprosy is:
Rifampicin: 600 mg once a month, supervised
Dapsone: 100 mg daily, self-administered
Clofazimine: 300 mg once a month, supervised
50 mg daily, self administered
Duration: 24 months
The above regimen is suitable for the treatment of all categories of multibacillary patients
except for those referred to alternative MDT regimens. Cases of relapse should be confirmed
by the referral centre and the patients should be retreated with the same regimen, since
drug resistance is unlikely.
Anti-Leprosy Drugs 179
7.16.2 Paucibacillary Leprosy
The six-month WHO MDT regimen for paucibacillary leprosy has yielded excellent results
wherever it has been appropriately used, and there is no convincing evidence to suggest
that it should be extended beyond six months. Scientists recommended that the regimen
be retained, with no changes in the duration or rhythm of therapy, or in the composition
or doses of drugs.
For adults, the recommended standard regimen for paucibacillary leprosy is:
Rifampicin : 600 mg once a month, supervised
Dapsone : 100 mg daily, self-administered
Duration : 6 months
If patients relapse, they should be retreated with the same regimen, provided their
disease is still paucibacillary. If, however, multibacillary leprosy is diagnosed at the time
of relapse, treatment should be in accordance with the recommended regimen for that
disease.
7.16.3 Alternative MDT Regimens
The availability of potent new drugs makes possible the formulation of alternative regimens
for use when it is impossible or inadvisable to employ the standard MDT regimens
described above. Some alternative MDT regimens are as follows.
Rifampicin resistance or toxicity
Multibacillary patients who have relapsed, and who have been shown to be infected with
rifampicin-resistant M. leprae (by testing in the mouse footed model), and those in whom
rifampicin has toxic effects require treatment with a new regimen. On the basis of the
available information, scientists have recommended the following regimen for adults:
Daily administration of 50 mg of clofazimine, together with two of the following
drugs, 400 mg of ofloxacin, 100 mg of minocycline, or 500 mg of clarithromycin for
6 months.
Daily administration of 50 mg of clofazimine, together with 100 mg of minocycline,
or 400 mg of ofloxacin for additional 18 months.
This regimen should be administered under direct supervision in a referral centre.
Severe Dapsone toxicity
If dapsone has severe toxic effects in any patient (paucibacillary or multibacillary), the
drug should be stopped immediately. No further modification of the regimen is required
for patients with multibacillary disease. However, clofazimine in the dosage employed in
the standard MDT regimen for multibacillary disease may be substituted for dapsone in
the regimen for paucibacillary disease for a period of 6 months.
180 Pharmaceutical Chemistry
Refusal to Accept Clofazimine
Every effort should be made to persuade multibacillary patients to agree to treatment with
clofazimine. When clofazimine is totally unacceptable owing to pigmentation of the skin,
the available evidence suggests that ofloxacin, 400 mg daily, or minocycline, 100 mg daily,
may be substituted for the clofazimine component of the standard MDT regimen. Because
of the limited information available, these drugs should be administered only under
supervision in a referral centre. In view of severe hepatotoxicity of ethionamide and
protionamide, the scientists considered that these drugs should no longer be recommended
as substitutes for clofazimine.
QUESTIONS
1. What are antileprotic agents? Explain with suitable examples.
2. What is dapsone? Explain its mode of action.
3. What is the synthesis of dapsone?
4. Explain the mode of action of dapsone.
5. What are the metabolites of dapsone and how does it metabolize?
6. What are the side effects of antileprosy drugs?
7. How does clofazimine work as an antileprotic agent?
8. Design the synthesis of clofazimine.
9. How does SAR study of clofazimine help to improve antileprotic activity? Explain.
10. How do metabolites of clofazimine affect the activity?
11. How can solapsone be synthesized?
12. Explain the ADME of the solapsone.
13. Write down the synthesis of ethionamide.
14. What is rifampicin? Explain the ADME.
15. How you will explain antileprotic macrolides with suitable examples?
16. Explain the metabolites of clarithromycin.
17. Write a short note on the minocycline and explain the synthesis.
18. How is the mode of action of minocycline similar to tetracycline?
19. What other drugs are used in leprosy treatment?
20. What is WHO recommendations on chemotherapic regimens?
8
HIV-AIDS: Antiviral Agents
8.1 INTRODUCTION
Viruses are non-cellular infectious agents incapable of self-replication; rather they must
take over a suitable host cell and use its genetic machinery in order to multiply. Such host
cells include bacterial, plant and animal cells, and there are over 400 viruses that are known
to infect humans.
Viral infections can be transmitted by aerial contact, as a result of an infected host
coughing or sneezing (viz., colds, chickenpox, flu, measles, mumps and viral pneumonia).
They may be transferable by close physical contact or transfusion of blood (viz., the viruses
responsible for genital herpes, AIDS and rabies). They can be transmitted by parasitic
arthropods, in particular ticks (viz., yellow fever and tick fever). They may be transmitted
via food and water, leading to diseases like hepatitis-A, polio and viral gastroenteritis.
Thus, viral infections have led to serious ‘plagues’ throughout the human history.
8.2 STRUCTURE OF VIRUSES
The viral nucleic acid is contained and protected within a protein coat called capsid which
is a combined unit of protein subunits called protomers (protomers generated in host cell
and capable to form capsid, the process is called self assembly). Once the capsid contains
the viral nucleic acid, the whole assembly is known as the nucleocapsid which may be
surrounded by carbohydrates and lipid layers. The complete structure is known as a virion
and could be varied in size from 10 nm to 400 nm and thus can be visible in electron
microscope (Fig. 8.1). In some viruses, the nucleocapsid may contain viral enzymes which
are crucial to its replication in the host cell.
Viruses contain either DNA or RNA as their genetic material, so there is a possibility of
two classifications of viruses either DNA viruses or RNA viruses. Most of DNA viruses
contain double stranded DNA, according to Watson-Crick base pairing. In contrast, most
RNA viruses contain single stranded RNA. If the base sequence of the latter is
complementary to viral messenger RNA, then it is known as the negative strand, but if the
base sequence of the viral RNA strand is identical to viral messenger RNA, then it is
referred to as a positive strand. The size of nucleic acid varies widely, with the smallest
viral genome coding for 3-4 proteins and the largest for over 100 proteins.