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102 Pharmaceutical Chemistry
4.6 SULFAMETHOXAZOLE
Sulfamethoxazole (SMZ or SMX) is an antibiotic belonging to the
sulfonamide family. It has been used since 1960s in the treatment
of various bacterial infections in humans and other species.
Sulfamethoxazole is used for treating various types of bacterial
H2N S
Sulfamethoxazole
O
HN
O
O
N
infections, especially acute chronic bronchitis, ear infections,
meningitis, urinary tract infections, gonorrhoea, etc. Sulfonamide has relatively
unfavourable pattern of tissue distribution thus usually it is used in combination with
trimethoprim for the treatment of various systemic bacterial infections. The combination
with trimethoprim is used mainly for chloroquine-resistant Plasmodium falciparum malaria
and also used as an alternative of amoxicillin-based antibiotics for the treatment of
sinusitis.
Sulfamethoxazole interferes with folic acid synthesis in susceptible bacteria and have a
similar chemical structure to PABA. They usually inhibit the conversion of PABA to the
coenzyme dihydrofolic acid by interfering with the nucleic acid synthesis of infected
microorganisms.
The synergistic combination of sulfometoxazole and trimethoprim (ratio 5:1) with
cotrimoxazole is specially used in the treatment of urinary tract infections. It is active
against oral anaerobes and Streptococcus, S. aureus, E. coli, H. Influenza, etc. It can also be
used to treat sinusitis, toxoplasmosis and P. pneumonia. It is sold under the trade names
Septrin, Bactrim, and Septra.
4.6.1 Specifications
Name : 4-Amino-N-(5-methylisoxazol-3-yl)-benzenesulfonamide, Sulfisomezole,
Sulfamethoxazol, 3-Sulfanilamido-5-methylisoxazole, Sulphamethoxazole
Molecular formula : C
10H11N3O3
S
Molecular weight : 253.279 g/mol
Melting point : 169°C
Physical state : White to slightly off-white crystalline powder
Solubility : Slightly soluble in water, benzene, chloroform, diethyl ether and
isopropanol, soluble in ethanol and methanol.
4.6.2 Synthesis of Sulfamethoxazole
The condensation reaction between p-Acetamidobenzene sulfonyl chloride (ASC) with
5-Methylisoxazol-3-ylamine followed by the hydrolysis gives an alkaline product
Sulfamethoxazole.
Antibiotic, Antibacterial and Antifungal Agents 103
O
O
S
NHCOCH
ASC
CH
Cl
H2N
Condensation
HCl
3
3
O
N
O
O
S
NHCOCH
H
N
N
O
Hydrolysis
CH
3
NaOH
3
H
O
O
S
NH
Sulfamethoxazole
N
N
2
O
CH
3
4.6.3 Mechanism of Action
Sulfonamides are structurally similar and competitive antagonists of PABA. PABA is an
important metabolite in DNA synthesis. They usually inhibit normal bacterial organisms
which utilize PABA for the synthesis of folic acid, by bacteriostatically mimicking the
PABA. Folic acid is not synthesized in humans, instead it can be taken from the dietary
supplements. This medication has selective toxicity towards bacterial cells over the normal
cells. It means they act only on those cells which are dependent on the synthesizing folic
acid. But excess use of sulfamethoxazole can develop bacterial resistance due to mutations
in the enzymes involved in folic acid synthesis, thus it prevents the drug to bind from
active site of the enzyme.
4.6.4 Adverse Effects and Treatment
Vomiting, nausea, diarrhoea, anorexia, etc., are the common adverse effects due to
sulfamethoxazole and other sulfonamides. Some relatively common side effects are fever,
skin rashes, exfoliative dermatitis, photosensitivity to skin and erythema nodosum. Some
severe side effects, viz., epidermal necrolysis, nephritis, potentially fatal, Stevens-Johnson
syndrome, tubular necrosis, renal failure, and hypersensitivity are associated with the use
of sulfamethoxazole. Sulfamethoxazole crystallization in urine may lead to lumbar pain,
oliguria, haematuria and anuria, which can be reduced by large liquid intake. Use of
sulphonamides and sulfamethoxazole can result occasionally in blood disorders, jaundice,
serum sickness, hypothrombinaemia, thrombocytopenia, liver necrosis, agranulocytosis,
hypersensitivity reactions, fibrosing alveolitis, eosinophilia, pulmonary eosinophilia and
vasculitis including polyarteritis nodosa.
Other possible adverse reactions could be headache, convulsions, mental depression,
dizziness, hypoglycaemia, meningitis, insomnia, hypothyrodism, fatigue and pancreatitis,
displacement of serum-bound bilirubin, etc.
4.7 SULFACETAMIDE
Sulfacetamide is a sulfa family antibiotic that is related to sulfamethoxazole and sulfadiazine.
The sulfonamides are synthetic bacteriostatic antibiotics with a potent activity against
104 Pharmaceutical Chemistry
Gram-positive and many Gram-negative microorganisms and sulfacetamide specially
have been used
resistant to the bacterial strains. Sulfacetamide inhibits bacteria by acting
as competitive inhibitors of PABA in the folic acid metabolism.
Most sulfonamides are readily absorbed orally, however more lipophilic
in urinary tract infections since 1941, however many individual species are
H
O
N
O
CH
S
O
3
sulfonamide salts are highly irritating and basic to the tissues and usually
distributed in all the tissues throughout the body. High concentration of
these drugs can be achieved in synovial, pleural, peritoneal, and ocular
NH
2
Sulfacetamide
fluids. Earlier this drug was used to treat meningitis but now it is restricted
due to some other effects.
It is specially used against the common bacterial eye pathogens, viz., Streptococcus
pneumoniae, E. coli, Haemophilus influenzae, Staphylococcus aureus, Klebsiella species,
Streptococcus (viridans group), and Enterobacter species. There is no report against
pathogens, viz., Pseudomonas aeruginosa, Neisseria species and Serratia marcescens, however
Staphylococcal species are completely resistant to the sulfa drugs.
4.7.1 Specification
Name : N-[(4-aminophenyl)sulfonyl]acetamide
Molecular formula : C
8H10N2O3
Molecular weight : 214.24 g/mol
Melting point : 181-184°C.
Physical status : Crystalline powder, white/yellowish-white.
Solubility : Water soluble, partially soluble in ethanol.
S
4.7.2 Synthesis of Sulfacetamide
Sulfacetamide can be synthesized either by direct alkylation of acetamide with 4-aminobenzenesulfonyl chloride, or reaction between acetic anhydride and 4-Aminobenzenesulfonamide followed by the deacetylation using Zn-NaOH.
O
Cl
O
S
NH
CH3CONH
2
2
H
O
N
O
S
NH
Sulfacetamide
CH
O
2
3
Zn-NaOH
H
C
3
H
O
N
CH
O
S
NH
O
3
O
(CH
CO)2O
3
O
NH
S
NH
2
2
O
4.7.3 Mechanism of Action
Sulfacetamide is another competitive inhibitor of bacteria by mimicking PABA which is an
essential precursor for bacterial growth (based on Woods-Fildes theory). The mechanism
Antibiotic, Antibacterial and Antifungal Agents 105
of action is almost similar to the above-mentioned drugs. This medication is specially used
to treat bacterial eye infections (such as conjunctivitis) while it won’t work for other types
of eye infections. Before applying this drug to the eyes, it is recommended that we should
use clean hands to avoid any contamination. Excess and misuse of any antibiotic can
develop decreased effectiveness.
4.7.4 Adverse Reactions
Excess oral use of this drug can lead to bacterial and fungal corneal ulcers. Other adverse
reactions such as burning, irritation and stinging can take place. Some less common
adverse effects include conjunctival hyperaemia, non-specific conjunctivitis, hepatic
necrosis, allergic reactions and secondary infections, fatal, Stevens-Johnson syndrome,
aplastic anemia, toxic epidermal necrolysis, fulminant agranulocytosis, other blood
dyscrasias, etc.
4.7.5 Side Effects
The common side effects are temporary blurred vision, eye burning, eye stinging and
redness, etc. Prolonged or repeated use of this drug can have serious side effects, viz., eye
infections, including fungal infections. Some rare but serious side effects can also occur,
viz., rashes on the nose and cheeks, fever, nausea, vomiting, throat pain, unusual bleeding,
weakness, abdominal pain, rapid breathing, swollen joints, anaemia, fast heartbeat, liver
problems, mouth sores, etc.
4.8 TRIMETHOPRIM
Trimethoprim, known as bacterial dihydrofolate reductase inhibitor,
belongs to the chemotherapeutic agents. It is a prophylactic drug used
to treat various bacterial infections, urinary tract infections caused by
Klebsiella species, Escherichia coli, Proteus mirabilis, Pneumocystis carinii
and traveller’s diarrhoea. Folic acid is an essential component for
haematopoiesis and thus trimethoprim can interfere with the folic
MeO
MeO
acid metabolism possibly by depression of hematopoiesis. Folic acid
is generally reduced to dihydrofolic acid and then finally reduced to
tetrahydrofolic acid, which is part of coenzyme and also acts as
coenzyme carrier in various metabolic functions. Thus, trimethoprim interferes in the
synthesis of tetrahydrofolic acid and finally leads to the inhibition of DNA nucleoside
synthesis.
Trimethoprim is usually used in combination with a sulfonamide drug, viz.,
sulfamethoxazole for synergistic effect (1:5). Almost all the sulfonamide antimicrobial
agents structurally mimic to PABA which is a key precursor called dihydropteroate
synthetase enzyme used for the synthesis of tetrahydrofolic acid (THF) in bacterial
microorganisms. The combination of trimethoprim and sulfamethoxazole (TMP-SMX)
NH
2
NN
OMe
Trimethoprim
NH
2
106 Pharmaceutical Chemistry
drugs interferes with the sequential steps in the metabolism of certain bacteria. Recent
studies show that very less use of sulfamethoxazole is due to bone marrow toxicity.
TMP-SMX is used in the treatment of respiratory tract, genitourinary, and gastrointestinal
infections caused by the probable bacteria such as E. coli, Klebsiella pneumonia, enterococci,
P. mirabilis, indole positive strains of Proteus spp. and urinary tract infections. TMP-SMX
is also used in the treatment of infections arising due to ampicillin-resistant Shigella spp.
and Salmonella typhi responsible for typhoid fever. Trimethoprim can be effectively used
when patients exhibit an allergic response to the sulphonamide component due to lipid
solubility of trimethoprim. Noncardial infections, typhoid fever, brucellosis, and
gonorrhoea have also been treated with this combination. This combination is the best
choice of antimicrobial therapy for both treatment and prevention of infection caused by
P. carinii (protozoan) which is responsible for serious pneumonitis in patients with
haematological malignancies and AIDS. Patients with AIDS are at increased risk of
symptoms such as rash, fever, hepatitis, and leukopenia. It is sometimes used alone as an
antimalarial.
4.8.1 Specification
Name : 5-(3,4,5-Trimethoxybenzyl)pyrimidine-2,4-diamine
Molecular formula : C
Molecular weight : 290.32 g/mol,
Melting point : 199–203°C
Physical state : White to yellowish powder with bitter taste
Solubility : Ethanol: Chloroform (hot 1:1), chloroform, propylene glycol,
14H18N4O3
methanol, very slightly soluble in water.
4.8.2 Synthesis of Trimethoprim
The reaction between malonic acid diethyl ester and substituted benzyl bromide under
strong basic condition gives 2-(3,4,5-trimethoxy-benzyl)-malonic acid diethyl ester which
further gives 3-(3,4,5-trimethoxy-phenyl)-propionic acid ethyl ester on reaction with NaCl.
This intermediate under formylation gives 3-hydroxy-2-(3,4,5-trimethoxy-benzyl)-acrylic
acid ethyl ester (or enol of the semi-aldehyde 3,4,5-trimethoxy-benzylmalonic ester), which
further reacts with guanidine under heterocyclization reaction that results in 2-amino-4hydroxy-5-(3,4,5-trimethoxybenzyl) pyrimidine. Hydroxyl group in 2-amino-4-hydroxy5-(3,4,5-trimethoxybenzyl) pyrimidine was then replaced using chlorine from phosphorus
oxychloride followed by the treatment of ammonia that results in the desired trimethoprim.
Trimethoprim can be synthesized via Knoevenagel condensation of ethyl cyanoacetate
with 3,4,5-trimethoxy benzaldehyde, which results in an ylidene derivative followed by
the reduction of double bond using H
acetic ester as an intermediate. Then after heterocyclization reaction with guanidine
followed by chlorination and reduction gives the desired trimethoprim.
/Pd-C catalyst giving 3,4,5-trimethoxybenzylcyano-
2
Antibiotic, Antibacterial and Antifungal Agents 107
O
O
EtO
O
O
O
Et
OEt
NaH
ArCH
Br
2
MeO
MeO
OMe
OOH
NH
2
NH
MeO
MeO
MeO
MeO
OEt
H2N
OMe
Alternative way to synthesize trimethoprim
NC
O
OEt
H
CO OCH
3
CHO
H
CO
3
OCH
OCH
3
3
OEt
OMe
OCH
NaCl
DMSO
NH
CN
3
O
OEt
MeO
MeO
HCOOEt
Et
O
2
OMe
NH
2
NN
OH
POCl
NH
MeO
3
3
MeO
2
NN
NH
2
OMe
Trimethoprim
CN
OEt
O
3
H2/Pd-C
H3CO OCH
OCH
OEt
O
3
3
NH
H2N NH
H2N
2
H3CO
OCH
N
OH
OCH
3
NH
2
N
1. POCl
3
3
2. H2/Pd-C
H2N NH
N
H3CO OCH
OCH
3
2
N
3
Trimethoprim
4.8.3 Side Effects
Trimethoprim usually decreases the levels of platelets (thrombocytopenia) by lowering
the folic acid level which finally causes megaloblastic anaemia. Trimethoprim acts like
amiloride in the host cell and antagonises the epithelial Na-channel in the distal-tubule
which finally can cause hyperkalaemia. Trimethoprim can also cause an artefactual rise in
the serum creatinine and increase the expression of Shiga toxin or verotoxin (verotoxin
produced by enterohaemorrhagic E. coli and Shigella dysenteriae) by competing with
108 Pharmaceutical Chemistry
creatinine for the secretion into the renal tubule. It can also affect the folate metabolism and
pregnancy due to easy penetration inside the placenta and sometimes it increases the risk
of early miscarriage in women.
Trimethoprim could lead to various other side effects, viz., headache, depression,
nausea, vomiting, confusion, hyperkalaemia, aseptic meningitis, skin problems (viz.,
Lyell’s syndrome, fixed local eruption, urticaria, exfoliative dermatitis, toxic erythema,
photodermatitis, erythema nodosum, erythema multiforme and necrotizing vasculitis,
etc.), renal infection (viz., acute interstitial nephritis, increased levels of creatinine, transient
blood urea and crystalluria), etc.
QUESTIONS
1. What are antibiotics?
2. What is the difference between antibiotic and antibacterial agents?
3. How do antimicrobial drugs exhibit antibacterial effects?
4. What are bacteriostatic and bactericidal drugs?
5. How can antibacterial agents act on bacterial cells?
6. Write the names of a few antibacterial agents.
7. What are antifungal agents and how do they work on the fungal cell?
8. What is chloramphenicol?
9. What is the synthesis of chloramphenicol?
10. How does chloramphenicol work on bacterial cells?
11. What are sulphonamides and how do they act on bacterial cells?
12. What is the synthesis of sulphonamides?
13. Write a short note on bioactivation of sulphonamides.
14. What is sulfamethoxazole and how does it act on bacterial cells?
15. What is the synthesis of sulfamethoxazole?
16. What is sulfacetamide and how does it act on bacterial cells?
17. What is the synthesis of sulfacetamide?
18. What is trimethoprim and how does it act on bacterial cells?
19. What is the synthesis of trimethoprim?
20. Write down the alternative synthesis of trimethoprim.
21. Why is p-amino benzoic acid replaced by sulfamethoxazole?
22. Why are sulfamethoxazole and trimethoprim given to a patient in a combination?
5
Central Nervous System Agents
5.1 INTRODUCTION
Most drugs acting on the nervous system do so by influencing the synaptic transmission
directly or indirectly, regardless of whether their aim is to alleviate disorders of memory,
mood, behaviour, cognition or movements. The drugs may pre-synaptically interfere in
the synthesis, degradation, reuptake and release of transmitters or post-synaptically in the
numbers, activity or localization of receptors. Certain drugs perform one or more of these
actions regarding one or several transmitters. Some drugs also seem to influence synaptic
functions individually by changing the expression of neurotrophic factors that (among
other tasks) govern synaptic plasticity.
The central nervous system (CNS) agents are one of the most widely studied and
sub-classified in Pharmacology. The CNS stimulants are used for cellular-impulse
transmission by increasing the level of the neurotransmitter norepinephrine. Narcotic
analgesics are generally used to suppress the pain of patient’s body by acting on the V- and
P-receptors. Non-narcotic drugs are specially used to suppress the inflammatory response
by reducing the level of prostaglandin synthesis. The action of cholinergic agent is carried
out either by increasing or decreasing the amount of acetylcholinesterase or acetylcholine.
Adrenergic agents are site-specific agents specially used to depress or promote D- and/or
E-responses by affecting the sympathetic nervous system.
Anticonvulsants may be used to decrease the level of acetylcholine or increase the
J-aminobutyric acid (GABA) levels, preventing Na
frequency and severity of seizures in patients suffering from epilepsy. Hypnotic and
sedative agents are involved in reducing the activity in the cortex or thalamus. Antidepressant agents act either by increasing the serotonin and norepinephrine levels in the
brain or by inhibiting the monoamine oxidase (MAO) production which is specially
involved in the degradation of the neurotransmitters. Antipsychotic agents reduce the
response of the medulla and inhibit the active site of dopamine receptor in the brain.
Carbamazepine is the best example of anticonvulsive antigen used in the treatment of
psychiatric conditions like treating bipolar diseases, diabetic neuropathy, controlling
neurogenic pain in trigeminal neuralgia and other neurological and psychiatric related
disorders. Valproic acid may also be used for the treatment of pain that arises due to
+
ion from entering the cell, decrease
110 Pharmaceutical Chemistry
migraine and bipolar diseases. Factors, viz., age, weight, water, electrolyte, protein, ADME
of particular patients can play a vital role to be an effective dosing and monitoring of
therapeutic use of drug.
Mostly, cytochrome P450 (CYP450) enzyme is responsible for the metabolism of such
drugs. Poor metabolizers (PM) increase drug accumulation in the blood, which can have
adverse effects on the patients therefore higher dose is needed to make more effective drug
while small dose is required for ultra metabolizers (UM). Prodrugs (viz., phenytoin,
warfarin, phenobarbital, codeine, dihydrocodeine, hydrocodone, oxycodone and tramadol)
are metabolized by CYP2C9 gene from CYP450 family. Thus, for better therapeutic plan
we need to focus on most common genetic variants of CYP2C9.
These medications are metabolized by the liver and excreted by the kidneys, however
risk is observed with patients having hepatic or renal diseases. Thus, before medication
doctor’s prescription is needed.
Drugs acting on CNS can be divided into the following criteria.
5.1.1 Narcotic Analgesics and Anti-Parkinsonian Drugs
5.1.1.1 Analgesics
Analgesic agents used to relieve pain arise due to multiple causes. Some drugs that relieve
pain due to a single cause are not analgesics class of drugs, viz., glyceryl trinitrate (angina
pectoris) and ergotamine (migraine). Analgesics can be classified into two sub-groups as
narcotic (opioid) analgesics and non-narcotic (opioid) analgesics (analgesics-antipyretics).
Narcotic drugs, mostly derived from morphine (active pharmaceutical ingredient of
opium), papaverine and codeine all alkaloids.
5.1.1.2 Drugs Used in the Treatment of Parkinsonism
In Parkinsonism, there is:
(a) Slow movement of body
(b) Rigidness of skeletal muscles in the body
(c) Resting tremors
(d) Abnormality of posture and gait
(e) Mood changes
(f) Salivation
(g) Masked face.
5.1.1.3 Causes of Parkinsonism
1. Idiopathic (any disease that is of uncertain or unknown origin may be termed
idiopathic. For example, diffuse idiopathic skeletal hyperostosis, acute idiopathic
polyneuritis, idiopathic pulmonary fibrosis, idiopathic scoliosis, etc.)
2. Arteriosclerotic (it is the thickening, hardening and loss of elasticity of the walls of
the arteries).
Central Nervous System Agents 111
3. Post-encephalitic [encephalitis (acute inflammation of the brain) with meningitis is
known as meningoencephalitis and it includes symptoms such as drowsiness,
fever, headache, confusion and fatigue].
4. Iatrogenic (caused by drugs), i.e., long use of large doses of chlorpromazine or
reserpine.
5. Parkinsonism is due to an imbalance between the levels of acetylcholine and
dopamine in the basal ganglia (substantia nigra, corpus striatum that are responsible
for motor control).
6. In Parkinsonism, the dopamine content is low so the cholinergic system is dominant.
5.1.1.4 Treatment of Parkinsonism
1. Cholinergic activity can be reduced by anticholinergic drugs (viz., Atropine or
Hyoscine),
2. Dopaminergic activity can be enhanced by using dopaminergic drugs (viz.,
Amantadine, Bromocryptine, Selegiline, and L-Dopa).
5.1.2 Sedative-hypnotics, Antipsychotic, Antidepressant Drugs and CNS Stimulants
5.1.2.1 Sedative-hypnotic Drugs
The sedative-hypnotic drugs have major therapeutic uses in sedation (disorders involving
anxiety) and sleeping disorders. An effective sedative (sometimes called anxiolytic, or
minor tranquilizer) has minor or no effect on mental functions because it reduces anxiety
and exerts a calming effect. These drugs usually force us towards abnormal sleep and help
to maintain the state of sleep which closely resembles natural sleep. Hypnotic effects
mostly include depression of the CNS. This effect can be increased by increasing the dose
of sedative-hypnotic drugs.
Examples:
1. Benzodiazepines
2. Buspirone
3. Zolpidem
4. Barbiturates
5. Chloral hydrate, paraldehyde
6. Ethyl alcohol (ethanol)
7. Other classes of drugs that may exert sedative effects include:
E-blocking drugs (e.g., Propranolol), which are used mainly to reduce physical
symptoms of anxiety (tremors, sweating, and palpitation). Their effect depends
on blockade of peripheral sympathetic responses rather than on any central
effects.
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