PHARMACEUTICAL CHEMISTRY -1

Lecture 3

I-
Antimalarial drugs

Asmaa Mohamed Atta, PhD

 Malaria
 Malaria is a life-threatening disease caused by
plasmodium parasite that and is transmitted to
human through the bites of infected female
Anopheles mosquitoes (malaria vector).
 The malarial parasite is a microorganism belonging to
the Plasmodium genus, of which there are four
species:
1- Plasmodium falciparum: cause approximately 50% of all malarial cases, the most
severe form of the disease because it infects up to 65% of the patient’s erythrocytes.
2- Plasmodium vivax: causing about 40% of all malarial cases, can be very chronic in
recurrence because it can reinfect liver cells.
3- Plasmodium malariae: causing only 10% of all malarial cases, relapses are very
common.
4- plasmodium ovale: the least common.
 Malaria
 The disease is currently associated with tropical countries but in the past, it was present
in Europe and North America.
 According to the World malaria report, there were 229 million cases of malaria in
2019. The estimated number of malaria deaths stood at 409 000 in 2019.
 Malaria life cycle
Stages of parasite that causes malaria after injection into its victim

Exoerythrocytic stages

Erythrocytic stages
 Classification of antimalarial drugs

4-Substituted
8-Aminoquinolines Antifolates Polycyclic
quinolines

Quinine Primaquine Pyrimethamine Artimisinin

Chloroquine Tafenoquine proguanil and its
semi-
Hydroxychloroquine synthetic
Mefloquine derivatives
 4-Substituted quinolines

Quinine Mefloquine
Quinoline

Chloroquine Hydroxychloroquine
 4-Substituted quinolines
Mechanism of action
 Hemoglobin is transported into the food vacuoles of the
plasmodium (pH 4.8 to 5.2) , where digestion of the
hemoglobin supplies the organism with a source of
amino acids.
 One of the products of this digestion is a free heme
called hematin (toxic to the plasmodium cell).
 The organism is capable of converting the hematin to
nontoxic hemozoin.
 The quinolines bind to hematin through a drug–heme
complex preventing further biocrystallization. Parasite cell
 Free toxic hematin is now present, which leads to the
death of the plasmodium.
 4-Substituted quinolines
Mechanism of action
The 4-substituted quinolines are effective against plasmodium in the
erythrocytic stage.

4- substituted quinoline
-

Degradation of hemoglobin by the Plasmodium organism to the toxic hematin and then to
the nontoxic dimer hemozoin.
 4-Substituted quinolines
1. Quinine
Alkene
(vinyl)
 Quinine is the most prevalent alkaloid present
(Levo isomer)
in the bark extracts of cinchona. Secondary alcohol Quinuclidine
 Quinine was the first known antimalarial.
(cyclic amine)

 Modification of the secondary alcohol through

oxidation or esterification diminishes
activity.

Quinidine, Dextro isomer of quinine, used as an

antiarrhythmic agent.
 4-Substituted quinolines
2. Chloroquine
 The most effective of the hundreds of 4-
aminoquinolines synthesized and tested during
World War II as potential antimalarials (1950s).

 Structure activity relationships showed that:

1- The chloro at the 7-position increased activity. (RS)-N'-(7-chloroquinolin-4-yl)-N,N-
2- Alkylation at C-3 and C-8 diminished activity. diethyl-pentane-1,4-diamine

 Unfortunately, from 1961 onwards, the parasite

has developed resistance to chloroquine the
drug is no longer effective in many malarial
infected areas of the world.
 4-Substituted quinolines
2. Chloroquine

Mechanism of resistance:
 Increase efflux of chloroquine from food
vacuole by multiple mutation in pfcrt
gene that codes for a transporter protein
(Plasmodium falciparum chloroquine-
resistance transporter (pfrcrt)
mechanism).
Parasite cell
 4-Substituted quinlolines
3. Hydroxychloroquine
Hydroxyethyl group

 The replacement of one of chloroquine N-ethyl groups with a hydroxyethyl

produced hydroxychloroquine.
 Used today for treatment of rheumatoid arthritis (auto-immune disease).
 4-Substituted quinolines
4. Mefloquine
Piperidine ring
 Exists as four optical isomers (two chiral center) with
nearly equal activity. *
*
 Characterized by having two trifloromethyl moeities
at positions 2 and 8.
 The lipophilic nature of the drug (due to presence of
trifloromethyl groups) increases tissue binding
long duration of action.
 CNS side effect: dizziness, vertigo, headache and
seizures.

 Mefloquine is an effective prophylactic agent against

Plasmodium falciparum (travelers coming into
regions of malaria and resident populations).
 8-Aminoquinolines
1. primaquine
 Primaquine is active against exoerthyrocytic stages
of parasite.
 It is the drug of choice for the treatment of relapsing
P.vivax and P.Ovale, eradicate hypnozoites remains
in the liver (radical treatment).
 It is recommended to use primiquine in combination (RS)-N-(6-methoxyquinolin-8-yl)
with chloroquine to eradicate the erythrocytic stages pentane-1,4-diamine
of malaria.

Note: Plasmodium, P. vivax and P. ovale produce

hypnozoites during their life cycle in the liver which are
able to reactivate the illness, a relapse, without any bite
of an infected mosquito.
 8-Aminoquinoline
2. Tafenoquine
 New 8-aminoquinoline derived from primaquine.
 Exhibit reduced toxicity and prolonged half life (≈16
days versus 4-8 hours for primquine, long acting).

 In 2018, FDA approved tafenoquine for:

1- Radical cure of Plasmodium vivax malaria.
2- Prophylaxis against all Plasmodium species and in any
malarious area.
 The long terminal half-life of tafenoquine offers
advantages in less frequent dosing for prophylaxis and
a single-dose course for treatment.
 Anti-folate (Dihydrofolate reductase inhibitors)
1. Pyrimethamine
P-chlorophenyl
 Potent inhibitor of dihydrofolate reductase (DHFR)
Ethyl group
inhibit reduction of dihydrofolate to
tetrahydrofolate which is necessary for the synthesis of
amino acids and nucleic acids.
 It showed higher affinity for binding to the DHFR Diamino
of plasmodium than to the host enzyme (selective to pyrimidine
plasmodium infections).

 The combination of pyrimethamine with

sulfadoxine (long-acting sulfonamide) which blocks
dihydrofolate synthesis by blocking incorporation of
para amino benzoic acid into the dihydrofolate, is
called Fansidar. Sulfadoxine
 Anti-folate
 Fansidar® produces sequential blockage of tetrahydrofolate synthesis.
 Used with quinine for the treatment and prevention of chloroquine-
resistant malaria.
 Anti-folate
2. Proguanil
Biguanide

Metabolism

Isopropyl group

Proguanil (prodrug) Cycloguanil (active form)

 Proguanil, developed in 1945 as early example of a prodrug.

 It metabolized to cycloguanil which is a dihydrofolate reductase inhibitor.
 Anti-folate
2. Proguanil naphthoquinone

 Proguanil is administrated in combination with

atavaquone (Malarone®).
 Atavaquone is a selective inhibitor of
plasmodium mitochondrial electron transport
Atavaquone
system (this deprives the cell of needed ATP).
 Malarone® acts as an effective prophylactic
and therapeutic antimalarial.
 Polycyclic antimalarial
Artimisinin
 The most recent additions to the drug therapy for malaria are
artemisinin and its derivatives.
 Artemisinin is isolated from Artemisia annua (sweetworm
wood), this material has been used by Chinese herbalists since
168 bc.
Endoperoxide
bridge

Trioxane ring
 Polycyclic antimalarial
Artimisinin
Mechanism of action
Within erythrocyte, endo-peroxide reacts which heme Fe (II) to generate series of
cytotoxic free radicals which are lethal to the plasmodium within the erythrocyte.
 Polycyclic antimalarial
Artimisinin semisynthetic derivatives

Artimisinin Dihydroartemisinin Artemether Sodium artesunate

 Dihydroartemisinin, artemether and sodium artesunate are all more active than
artemisinin itself.
 SAR: 1- The endoperoxide group in the trioxane ring was the essential group
required for antimalarial activity (pharmacophore).
2-The lactone carbonyl group of artemisinin is not essential to its antimalarial activity.
 Polycyclic antimalarial
Artimisinin and its semisynthetic derivatives

 These compounds have gametocytocidal activity as well as activity

against all erythrocytic stages of the parasites.
 These agents are short acting, with relatively short half-lives.
 Little or no resistance has been reported.
 Artemisinin-based combination therapy (ACT) have been reported
to show cure rates of greater than 90% and are now accepted as the
best treatments for falciparum malaria (such as artesunate–
mefloquine combination).
PHARMACEUTICAL CHEMISTRY -1
Lecture 3
II- Anti-
Mycobacterial drugs

Asmaa Mohamed Atta, PhD

 Introduction
 Mycobacterium, genus of rod-shaped bacteria
of the family Mycobacteriaceae. This genus
includes pathogens known to cause serious
diseases in mammals, including tuberculosis
(Mycobacterium tuberculosis) and leprosy
(Mycobacterium leprae) in humans. Mycobacterium tuberculosis

 The name Mycobacterium, which means

‘‘fungus bacterium’ to describes the way
mycobacteria have been observed to grow in a
mold-like fashion on the surface of cultures.

Mycobacterium leprae
 Introduction
 The characteristic feature of all
Mycobacterium species is that the
cell wall is thicker than in many
other bacteria, being hydrophobic,
waxy, and rich in mycolic acids.
 The high lipid concentration in the
cell wall accounts for its
impermeability and resistance to
antimicrobial agents, acid, base and
alcohols .
 Outline

Tuberculosis
Leprosy
(TB)

Antituberculosis Antileprotic
drugs drugs
(First and second (dapsone and
line agents) clofazimine)
 1- Tuberculosis (TB)

 Worldwide, TB is the 13th

leading cause of death and the
second leading infectious killer
after COVID-19 (above
HIV/AIDS).
 In 2020, an estimated 9.9 million
people fell ill with
tuberculosis(TB) worldwide.
Despite being a preventable and
curable disease, a total of 1.5
million people died from TB.
 1-Tuberculosis
 A chronic bacterial infection caused by Mycobacterium tuberculosis.
 Mycobacterium tuberculosis was discovered by Robert Koch in 1882.
 Tuberculosis is transmitted primarily through inhaling tiny droplets
expelled during coughing , sneezing or talking of infected persons.
 TB is a disease that mainly affects the lungs (pulmonary TB-80% to 85%
of the cases).
 Symptoms of Pulmonary TB: bad cough lasts for at least 3 month
(coughing up blood or mucus from the lungs), chest pain, breathlessness.
 In pulmonary TB, the bacilli reach the alveoli and are ingested by
pulmonary macrophages fibroblasts to enclose the infection site
formation of granulomas. The infection can lie dormant for years and then
reappear later.
 M. tuberculosis can spread through the bloodstream and the lymphatic
system to the brain, bones, eyes, and skin (Extrapulmonary TB).
 Antituberculosis drugs
 Successful treatment should have bactericidal action against all stages (rapidly
rapidly growing bacilli and dormant) of the organisms.
 Thus, TB therapy is based on use of combination therapy over an extended period of
time (6-9 month).

Classification of Anti-tuberculosis drugs depending on tolerance and clinical

efficacy:
First-line agents: Isoniazid, Rifamycin antibiotics (Rifampin or Rifapentine),
Pyrazinamide (PZA) and Ethambutol (EMB).
 They have the maximum effect with minimal toxicity.
Second-line agents: Ethionamide, P-aminosalicylic acid, Streptomycin, kanamycin,
Capreomycin, Cycloserine and Levofloxacin.
 These drugs have weaker effects and are more toxic for humans. They are used in
patients where the TB mycobacterium is resistant to first-line drugs.
 Antituberculosis drugs
First line drugs Isoniazid (INH) (Isonicotinic Acid Hydrazide)

 Effective antibacterial agent, discovered in the 1950s.

 The primary drug for treatment of M. tuberculosis (in
combination with rifampin, pyrazinamide and
ethambutol).
 Its action is bactericidal against growing bacilli, but
bacteriostatic against resting ones.
pyridine-4-carbohydrazide
 Co-administration of pyridoxine (vitamin B6) is
reported to prevent the symptoms of peripheral
neuritis (antagonism of a coenzyme action of
pyridoxal phosphate).
 Antituberculosis drugs
First line drugs
Isoniazide (INH)
Mechanism of action
 INH is a prodrug that is activated through oxidation reaction by mycobacterium
catalase-peroxidase enzyme (katG) to reactive species (e.g Isonicotinoyl radical)
that acylates NADH.
 The acylated NADH is no longer capable of catalyzing the reduction of
unsaturated fatty acids, which are essential for the synthesis of the mycolic acids
(an essential cell wall component of M. tuberculosis).
 Antituberculosis drugs
First line drugs
Isoniazide (INH)

Synthesis:

Isonicotinic acid Isonicotinic acid ester

 Antituberculosis drugs
First line drugs
Pyrazinamide
 Bioisostere of nicotinamide.
 Bactericidal activity against non replicating persister
bacilli (encapsulated form).
 Its activity is pH dependent with good in vivo activity at
pH 5.5 (that exists in granulomas). pyrazine-2-carboxamide
 An essential component in combination with INH and
rifampin for the treatment of TB.

SAR:
 Substitution on the pyrazine ring or use of alternate
heterocyclic aromatic rings reduce activity.
Nicotinamide
 Antituberculosis drugs
First line drugs
Pyrazinamide

Mechanism of action:
 Converted by mycobacterium pyrazinamidase to pyrazinoic acid intracellularly
(probably a prodrug).
 Pyrazinoic acid can lower the pH in the surroundings of the M. tuberculosis to
such an extent that the organism is unable to grow.
 Antituberculosis drugs
First line drugs
Ethambutol
 Sterospecific, Dextro enantiomer, which is 200 to 500
fold more active than its Levo enantiomer. *
 Active only against dividing mycobacteria and has no *
effect on encapsulated form.

Mechanism of action:
 Inhibit the synthesis of the arabinogalactan portion of the cell wall inhibit
incorporation of mycolic acids into the cell wall damage to cell wall.
 Damge to cell wall created by ethambutol improves the cell penetration of
other intracellular drugs (such as rifampin) resulting in increased biological activity.
 Antituberculosis drugs
Second line drugs Ethionamide

2-ethylpyridine-4-carbothioamide

 Bactericidal against M. tuberculosis and Mycobacterium leprae.

 The mechanism of action is similar to that of INH.
 A prodrug that is converted via oxidation by catalase-peroxidase to an active
acylating agent (ethionamide sulfoxide).
 Adverse effects: GI irritation and CNS effects.
 Antituberculosis drugs
Second line drugs
p-Aminosalicylic Acid (PAS)

4-Amino-2-hydroxybenzoic acid

 Act as an antimetabolite interfering with the incorporation of p-

aminobenzoic acid into folic acid.
 As a bacteriostatic agent, PAS is used at a dose of up to 12 g/day, which
causes considerable GI irritation.
 Hypersensitivity reactions occur in 5% - 10% of the patients.
 Antituberculosis drugs
 The long period of treatment has led to the development of drug resistant TB,
multidrug-resistant MDR-TB (resistance to INH and RIF).
 Treatment: a combination of an aminoglycoside (streptomycin, kanamycin,
amikacin or capreomycin), a fluoroquinolone (ofloxacin, levofloxacin, or
moxifloxacin), along with ethambutol, pyrazinamide and ethionamide.
 If resistance to ethambutol and pyrazinamide, then p-aminosalicylic acid and
cycloserine are added to the previous indicated drug list of an
aminoglycoside, a fluoroquinolone and ethionamide.
 2- Leprosy
 Leprosy (Hansen's disease) is a chronic disease caused by
Mycobacterium leprae that classically results in varying
skin lesions with peripheral nerve damage.
 Leprosy is most common in tropical areas of the world,
notably India and Brazil.
 Leprosy mainly affects the skin, the peripheral nerves,
upper respiratory tract causing skin ulcers, nerve damage,
and muscle weakness.
 The disease isn’t highly infectious and is usually spread by
breathing airborne droplets expelled during coughing or
sneezing of infected persons.
 Antileprotic drugs
Dapsone
4,4'-Diaminodiphenylsulfone

 Dapsone was first introduced into the treatment of leprosy in 1943.

 A bacteriostatic agent act in a manner similar to that of sulphonamides through
competitive inhibition of p-aminobenzoic acid incorporation into folic acid.
 Used often in combination with clofazimine and rifampin.
 Antileprotic drugs
Clofazimine

 Phenazine derivative, dark red dye that leads to

pigmentation of the skin, discoloration of the
feces, eyelid lining, sputum, sweat, tears, and
urine.
 Frequently used in combination with other drugs,
such as dapsone or rifampin.
 very slow elimination from the body (half-life is
estimated to 69 days).