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Anti-infective Agents 307
Uses: It is active against late hepatic stages (hypnozoites, schizonts), eliminates tissue
(exo-erythrocytic) malarial infection, preventing the development of the erythrocytic forms of the
parasite which are responsible for relapses in Plasmodium vivax and Plasmodium ovale malaria.
Storage and Stability: Store between 15°C to 30°C. Keep out of reach and sight of children.
Formulation: Primaquine phosphate Tablets: 26.3 mg (equivalent to 15 mg base)
Officials:
➢ Primaquine Phosphate, I.P.
➢ Primaquine Phosphate Tablet, I.P.
11.5.4 Mefloquine
Brand Name: Lariam
Mefloquine is an antimalarial drug used in the prophylaxis and treatment of malaria caused
by Plasmodium falciparum and Plasmodium vivax.
Chemistry and Structure: Mefloquine is a derivative of 4-aminoquinolines. It is an
organofluorine compound that posses quinoline bearing trifluoromethyl substituent at positions
2 and 8 as well as a (2-piperidinyl) hydroxymethyl substituent at position 4.
Mefloquine exist in four stereoisomers due to the presence of two asymmetric carbon centres in
the molecule. It is currently manufactured and sold as a racemate of the (R, S)– and (S, R)–
enantiomers by Hoffman-La Roche, a Swiss pharmaceutical company. Plasma concentrations of
the (–)-enantiomer are significantly higher than those for the (+)-enantiomer.
Nomenclature: [2, 8-bis (trifluoromethyl) quinolin-4-yl]-(2-piperidyl) methanol
Properties: The drug occurs as white to almost white crystalline powder. Soluble in water is 0.35
g/100 ml at 25°C. The pH of a 1% aqueous suspension is 5.0 to 6.5. The pka value is
approximately 9. The substance melts at approximately 252°C with decomposition.
Uses: It is used for the prevention and therapy of P. falciparum malaria. Mefloquine therapy is
associated with a low rate of transient and asymptomatic serum enzyme elevations and is a rare
cause of clinically apparent acute liver injury. It works by interfering with the growth of parasites
in the red blood cells of the human body.
Storage and Stability: It should be stored in a tight closed container between 15°C to 30°C.
Keep away from heat, moisture, and direct light. Keep in the blister until consumed. Discard
outdated medicine or medicine no longer needed.
308 Text Book of Pharmaceutical Chemistry
Dosage Forms: Oral tablet (250 mg). It is available as 250 mg tablets of Mefloquine
hydrochloride (equivalent to 228.0 mg of the free base) for oral administration. The
recommended dose of Mefloquine is approximately 5 mg/kg once weekly (to a maximum of 250
mg).
➢ Adults and children weighing over 45 kg: In persons over 45 kg, the prophylactic dose
is 250 mg of Mefloquine (1 Mefloquine tablet) once weekly.
➢ Children and adults weighing less than 45 kg: The weekly dose decreases in
proportion to body weight.
11.5.5 Cycloguanil
Cycloguanil is a dihydrofolate reductase inhibitor and is a metabolite of the drug Proguanil.
Proguanil is a prodrug that is metabolized to its main active metabolite, cycloguanil, via
CYP2C19. There is significant variation in Proguanil pharmacokinetics. CYP2C19 is the
predominant enzyme catalyzing the bioactivation of Proguanil to Cycloguanil.
Chemistry and Structure: Structurally, it consists of triazine ring in which a 1, 6-dihydro-1,3,5-
triazine ring is substituted at N-1 by a 4-chlorophenyl group, at C-2 and C-4 by amino groups and
at C-6 by gem-dimethyl groups.
Nomenclature: 1-(4-Chlorophenyl)-1,6-dihydro-6,6-dimethyl-1,3,5-triazine-2,4-diamine.
Uses: It is one of the antimalarial drugs that act on both the erythrocytic and on the pre-
erythrocytic (hepatic) forms of the malaria parasites. Whilst cycloguanil is not currently in
general use as an antimalarial, the continuous development of resistance to current antimalarial
drugs has led to carry on interest in studying the use of cycloguanil in combination with other
drugs.
11.5.6 Pyrimethamine
Brand Name: Daraprim
Pyrimethamine is an antiparasite medication that helps to prevent parasites from growing and
reproducing in the body. It is a synthetic derivative of ethyl-pyrimidine with potent antimalarial
properties. It act by a competitive inhibition of dihydrofolate reductase (DHFR), a key enzyme in
the redox cycle for production of tetrahydrofolate, a cofactor that is required for the synthesis of
DNA and proteins. This medicine is often used in combination with other antimalarials for the
treatment of uncomplicated falciparum malaria.
Anti-infective Agents 309
Chemistry and Structure: It is an aminopyrimidine that is pyrimidine-2,4-diamine which is
substituted at position 5 by a p-chlorophenyl group and at position 6 by an ethyl group. It is a
competitive inhibitor of dihydrofolate reductase (DHFR). Pyrimidinediamine has the following
structural formula:
Nomenclature: 5-(4-chlorophenyl)-6-ethylpyrimidine-2,4-diamine
Properties: It occurs as odorless and tasteless white crystalline solid. It is soluble in organic
solvents such as DMSO and dimethyl formamide and pyrimethamine; and sparingly soluble in
aqueous buffer.
Uses: Pyrimethamine is used to treat a serious parasite infection (toxoplasmosis) of the body, brain,
or eye or to prevent toxoplasmosis infection in people with HIV infection. When used to treat
malaria, pyrimethamine should be used together with a faster-acting antimalarial medicine such
as Chloroquine or Quinine.
Dosage Forms: Oral tablet (25 mg). Each scored tablet contains 25 mg Pyrimethamine and the
inactive ingredients corn and potato starch, lactose, and magnesium stearate.
➢ Treatment of Toxoplasmosis: Pyrimethamine is suggested for the treatment of
toxoplasmosis when used together with a sulfonamide, since synergism exists with this
combination.
➢ Treatment of Acute Malaria: It is also indicated for the treatment of acute malaria.
It should not be used alone to treat acute malaria. Fast-acting schizonticides such as
Chloroquine or Quinine are indicated, and preferable for the treatment of acute malaria.
Although, pyrimethamine in combination with a sulfonamide (e.g., sulfadoxine) will
initiate transmission control and suppression of susceptible strains of plasmodia.
➢ Chemoprophylaxis of Malaria: It is indicated for the chemoprophylaxis of malaria due
to susceptible strains of plasmodia.
Officials:
➢ Pyrimethamine, I.P.
➢ Pyrimethamine Tablet, I.P.
➢ Pyrimethamine and Sulphadoxin Tablet, I.P.
11.5.7 Artemisinin
Brand Names: Alaxin, Armiqin, Artequik, Dimisinex
Artemisinin is a sesquiterpene lactone structure derived from extracts of sweet wormwood
(Artemisia annua) and is well established for the treatment of malaria, including highly drug-
resistant strain. An unusual component of the artemisinin molecules is an endoperoxide 1,2,4-
trioxane ring. This is the main antimalarial centre of the molecule.
310 Text Book of Pharmaceutical Chemistry
Structure:
Nomenclature: (3R,5aS,6R,8aS,9R,12S,12aR)-3,6,9-trimethyloctahydro-3,12-epoxypyrano [4,3-
j] [1,2] benzodioxepin-10(3H)-one
Properties: Artemisinin appears as white highly crystalline compound with needle-like crystals
with melting point 151°C to 153°C. It is poorly soluble in oil or water. So, it can only be given by
the enteral rout. It dissolves in acetone, ethanol, ether, and petroleum ether and alkali solution.
NaOH titration of Artemisinin consumes one equivalent.
Uses: Artemisinin is used to treat fevers. It is also an effective treatment for malaria. It is also
used for the treatment of inflammation or bacterial infections or headaches.
Dosage: The conventional dosage regimen for orally administered Artemisinin is 500-1000 mg
(10-20 mg/kg) on the first day, followed by 500 mg daily for 4 days. Artemisinin suppositories
have been given to patients with severe Falciparum malaria, at doses of 600-1200 mg initially,
followed by 400-600 mg 4 hours later and 400-800 mg daily for 3 days. Generally, Mefloquine
15-25 mg/kg is given 24-72 hours after commencement of Artemisinin therapy.
Storage: Artemisinin should be kept in a well-closed container, protected from light and stored in
a cool place. Its melting point is 151°C to 154°C.
11.6 SULFONAMIDES
11.6.1 Introduction
Sulfonamides or sulfa-related group of antibiotics are one of the oldest classes of
antimicrobial drugs, which are used in the treatment of bacterial infection and some fungal
infections. These are synthetic bacteriostatic agents with a wide spectrum of activity against most
gram-positive and many gram-negative organisms.
Chemically, all the sulfonamide containing the sulfonamide (sulfanilamide, SO
2
-NH
2
) and
functional group are attached to the aniline. The structure is related to the p-amino benzoic acid
(PABA).
Properties of Sulfonamides
All sulfa drugs are oily liquids or white crystalline solids except quinoxaline (yellow) that are
almost always prepared by the reaction of a sulfonyl chloride with ammonia or an amine, most
commonly in the presence of caustic alkali. The first sulfonamide drug, introduced in 1932, was a
red azo dye called Prontosil.
Anti-infective Agents 311
Chemically, sulfa drugs are amphoteric. They generally behave as weak organic acid with
pKa 4.79 to 8.56. They are insoluble in water; their solubility is increased at alkaline pH. Sodium
salts are however easily soluble in water. The sulfacetamide is neutral in pH and is used to
combat eye infections. The general structure of sulfanilamide and PABA is given in Fig. 11.1.
Sulfanilamide and its derivatives are popularly known as sulfonamide or sulfa drug.
Fig. 11.1: General structure of Sulphanilamide and PABA
Classification of Sulphonamides
I. Based on duration of action:
1. Short acting (6-9 hours): Sulfadiazine, Sulfadimidine, Sulfacetamide, Sulfacytine,
Sulfisoxazole.
2. Intermediate acting (10-12 hours): Sulfamethoxazole, Sulfamoxole.
3. Long acting (7 days): Sulfadoxine, Sulfamethopyrazine, Sulfadimethoxine.
4. Topically used: Mafenide, Silver sulfadiazine, Sulphacetamide.
5. Ulcerative colitis: Sulfasalazine
II. Based on their site of action:
1. Systemic sulphonamides: Sulfadimidine, Sulfapyridine, Sulfathiazole, Sulfamerazine,
Sulfaphenazole.
2. Renal sulphonamides: Sulfisoxazole (Sulfafurazole), Sulfasomidine.
3. Topical sulfonamides: Sulfamylon, Silver sulfadiazine.
4. Ophthalmic sulfonamide: Sodium sulfacetamide
5. Gut acting sulfonamides: Succinylsulfathiazole, Phthalylsulfathiazole, Sulfaguanidine
III. Based on chemical structure:
1. Both N
1
and N
4
substituted sulphonamides: Succinyl sulfathiazole, Phthalyl
sulfathiazole.
2. N
1
substituted sulphonamides: Sulfapyridine, Sulfathiazole, Sulfadimidine
(Sulfamethazine), Sulfamerazine, Sulfaphenazole.
3. N
4
substituted sulphonamides: Protonsil, Sulphaguanidine.
312 Text Book of Pharmaceutical Chemistry
Sulfonamides are the antibiotics that are structurally related to p-aminobenzoic acid (PABA),
a precursor in bacterial DHF synthesis. These antibiotics competitively inhibit the utilization of
PABA, and hence, DHF synthesis. Because most bacteria cannot take up exogenous folate, they
are depleted of DHF.
Table 11.1: Structural Features of Sulphonamides with their Therapeutic Uses
Sr.
No.
Name of
Sulpha Drugs
R
1
R
2
Therapeutic
Uses
1
Sulphathiazole
-H
Vaginal
infections and for
disinfecting home
aquariums
2
Sulphacetamide
-COCH
3
-H
Ophthalmic uses
3
Sulphadimidine
-H
Haemorrhagic
septicaemia
4
Sulphaphenazole
-H
Systemic
sulphonamide
5
Sulphamerazine
-H
Systemic
sulphonamide
6
Phthalylsulphathiazole
Used in intestinal
infection
Anti-infective Agents 313
Sr.
No.
Name of
Sulpha Drugs
R
1
R
2
Therapeutic
Uses
7
Sulphadimethoxide
-H
Respiratory,
urinary tract,
enteric, and soft
tissue infections
8
Sulphamethoxypyridazine
-H
Used in the
treatment of
vaginal irritation
and also in
Dermatitis
herpetiformis
9
Sulphamethoxydiazine
-H
Used as a
leprostatic agent
10
Sulphamethiazole
-H
Urinary tract
infections
11
Sulphamethoxazole
-H
Used in bacterial
infections (such
as middle ear,
urine, respiratory,
and intestinal
infections)
12
Sulphisoxazole
-H
Used in bladder
infections, ear
infections, or
meningitis.
13
Sulphaguanidine
-H
Used in GIT
14
Sulphapyridine
-H
Controls
dermatitis
314 Text Book of Pharmaceutical Chemistry
Sr.
No.
Name of
Sulpha Drugs
R
1
R
2
Therapeutic
Uses
15
Sulphadiazene
-H
Used in
meningitis
16
Sulphalene
-H
Used for
respiratory and
urinary tract
infection
17
Succinyl Sulphathiazole
Used in
Intestinal
infection
11.6.2 Sulphanilamide
Brand Name: AVC
Generic Name: Sulfanilamide
Sulfanilamide is a sulphonamide drug in which the sulfamoyl functional group is attached
to aniline at the 4th position. It exhibits broad-spectrum activity against systemic bacterial
disease.
Nomenclature: 4-amino-benzene sulphonamide
Properties: It occurs as white to almost white crystalline powder. It is insoluble in chloroform,
ether and benzene and petroleum ether; and soluble in glycerol and propylene.
Uses: Sulphanilamide is used topically and vaginally for the treatment of susceptible infections,
often in combination with other drugs Micromedex. It is primarily used as vaginal anti-infective
and topically used in the treatment of vaginal yeast infections. glycol, hydrochloric acid, solution
of potassium and sodium hydroxide.
Storage: It should be stored in a cool, dry place. It should be kept in containers tightly closed.
It should be protected from light and stored under an inert atmosphere. It should be used with
adequate ventilation. Minimize dust generation and accumulation.
Anti-infective Agents 315
Chemical Stability: Air sensitive. Light sensitive. Incompatibilities with other materials. Strong
oxidizing agents.
11.6.3 Sulfadiazine
Brand Names: Lantrisul, Neotrizine, Sulfa-Triple, Sulfadiazine, Sulfaloid, Sulfonamides Duplex,
Sulfose, Terfonyl, Triple Sulfa, Triple Sulfas, Triple Sulfoid
Sulfadiazine is a sulphonamide consisting of pyrimidine with a 4-aminobenzenesulfonamido
group at the 2nd position. It has a role as an antimicrobial agent, an anti-infective agent,
a coccidiostat, an antiprotozoal drug.
Nomenclature: 4-amino-N-pyrimidin-2-ylbenzenesulfonamide
Properties: Sulfadiazine occurs as white, yellowish white or pinkish white odorless crystalline
powder. It is poorly soluble in water (1 g in about 13,000 ml water), and sparingly soluble in
ethanol and acetone. It is readily soluble in dilute mineral acid and bases.
Uses: It is used for the treatment of many different types of infection such as urinary tract
infections, ear infections, meningococcal meningitis, malaria, chancroid, trachoma, inclusion
conjunctivitis, nocardiosis, toxoplasmosis encephalitis and rheumatic fever.
Dosage Forms: Oral tablet (500 mg).
➢ Adult Dosage: Initially 2-4 g. Maintenance: 2-4 g divided into 3-6 doses every 24 hours.
➢ Children Dosage: 150 mg/kg divided into 4-6 doses every 24 hours, maximum 6 g/24
hours. Rheumatic fever prophylaxis: <30 kg: 500 mg every 24 hours; >30 kg: 1 g every
24 hours.
Storage: Store at room temperature between 59-86°F (15°C to 30°C). Store the medicine in a
closed container at room temperature, away from heat, moisture and direct light.
Officials:
➢ Sulfadiazine Tablet, B.P.
➢ Sulfadiazine Injection, B.P.
➢ Sulfadiazine Tablet, I.P.
11.6.4 Sulfamethoxazole
Generic Name: Sulfamethoxazole
Brand Names: Bactrim, Septra, Sulfatrim
316 Text Book of Pharmaceutical Chemistry
Nomenclature: 4-amino-N-(5-methyl-1,2-oxazol-3-yl) benzene sulfonamide
Properties: Sulfamethoxazole is a tasteless, odorless, almost white crystalline powder. It is
slightly soluble in water and benzene; slightly soluble in chloroform, diethyl ether and
isopropanol; soluble in ethanol and methanol.
Uses: It is used to treat acute, recurrent or chronic urinary tract infections (primarily
pyelonephritis, pyelitis and cystitis) due to susceptible organisms (usually E. coli, Klebsiella-
Enterobacter, Staphylococcus, Proteus mirabilis and, less frequently, Proteus vulgaris) in the
absence of obstructive uropathy or foreign bodies.
Dosage Forms:
➢ Adult dose: Initially 2 g, followed by 1 g twice a day.
➢ Pediatric dose: (> 1 month of age) oral dose is initially 50-60 mg/kg bw, followed by
25-30 mg/kg bw every 12 hours; the total dose should not exceed 75 mg/kg bw per day.
Storage: Store in a closed container at room temperature, away from heat, moisture, and direct
light. Keep from freezing. Keep out of the reach of children.
Officials:
➢ Sulfamethoxazole, I.P.
➢ Trimethoprim and Sulfamethoxazole Tablet, I.P.
➢ Trimethoprim and Sulfamethoxazole Oral Suspension, I.P.
11.6.5 Sulfacetamide
Generic Name: Sulfacetamide
Sulfacetamide is an antibiotic containing a benzenesulfonamide moiety with an amine group
attached to the benzene ring. Sulfacetamide, as a medicine, is available as solution, eye drops,
lotion, and powder. It can also be found in the form of the sodium salt, sulfacetamide sodium. It is
available in fixed-dose combinations with Prednisolone.
The structure of sulfacetamide is a sulfonamide that is sulfanilamide acylated on the
sulfonamide nitrogen. It has a role as an antimicrobial agent and an anti-infective agent. It has
broad-spectrum of activity.