MEDICINAL CHEMISTRY OF

ANTI-FOLATE AND ANTI-

FUNGAL DRUGS
GROUP NAME ID

1.Nesredin Abdi 1687/11

2.Rahel Negasa 1688/11

3. Samuel Aklilu 1690/11

4. Sura Belay
1692/11
5. Tade Yeshitila
1693/11
6. Tsega Tariku
1695/11
7.Umer Ferhad
1696/11

8.Yakob Tujuba 1697/11

ANTI- FOLATE DRUGS
 ANTIFOLATE DRUGS
CLASSIFICATION
A. Sulfonamides
 The sulfonamides have a common chemical nucleus
resembling p-aminobenzoic acid (PABA).
MECHANISMS OF ACTION
• The sulfonamides are
They inhibit the folic acid synthesis
bacteriostatic inhibitors of p-Aminobenzoic acid (PABA)
folic acid synthesis.
Sulfonamides
• As antimetabolites of PABA, Dihydropteroat (compete with
e synthase PABA)
they are competitive
inhibitors of dihydropteroate Dihydrofolic acid

synthase. Dihydrofolat Trimethoprim,

e reductase pyrimethamine
• The selective toxicity of
Tetrahydrofolic acid
sulfonamides results from the
inability of mammalian cells
to synthesize folic acid; they
Purines
must use preformed folic acid
that is present in the diet.
DNA
 CLINICAL USE
Sulfonamides (now rarely used by themselves)
• They are active against gr(-) and gr(+) organisms
• They are used for the condition that:
simple urinary tract infections - sulfisoxasole
ocular infections - sulfacetamide
burn infections - silver sulfadiazine
ulcerative colitis - sulfasalazine
rheumatoid arthritis - sulfasalazine
toxoplasmosis - oral sulfasalazine plus
pyrimethamine (a dihdyrofolate reductase inhibitor) plus
folic acid
 TOXICITY
Sulfonamides
• Hypersensitivity: allergic reactions including skin
rashes and fever. Cross allergy may occur wit
chemically related drugs (thiazides, hypoglycemics)
• GI: nausea, vomiting and diarrhea
• Hematotoxicity: they are rare. Granulocytopenia,
thrombocytopenia and aplastic anemia
• Nephrotoxicity: they may precipitate in the urine at
acidic pH, causing crystalluria and hematuria
B.Trımethoprım & Pyrımethamıne

Trimethoprim
•This drug is structurally similar to folic acid.
•It is a weak base and is trapped in acidic environments, reaching
high concentrations in prostatic and vaginal fluids.
•A large fraction of trimethoprim is excreted unchanged in the
urine.
•The half-life of this drug is similar to that of sulfamethoxazole(10
—12 h).
Trimethoprim is a selective inhibitor of bacterial
dihydrofolate reducate that prevents formation of the
active tetrahydro form of folic acid.

CO-TRIMOXAZOLE (trimethoprim plus

sulfamethoxazole)
• When the 2 drugs are used in combination,
antimicrobial synergy results from the sequential
blockade of folate synthesis.
• The drug combination is bactericidal against
susceptible organisms
 TOXICITY
• Trimethoprim may cause the predictable adverse effects
of an antifolate drug, including megaloblastic anemia,
leukopenia, and granulocytopenia.
• These effects are usually ameliorated by supplementary
folinic acid.
• The combination of TMP-SMX may cause any of the
adverse effects associated with the sulfonamides.
• AIDS patients given-SMX have a high incidence of
adverse effects, including fever, rashes, leukopenia
Resistance
Production of a mutated dihydropteroate
synthetase that has reduced affinity for
binding of sulfonamides and mutuation of
dihydrofolate reductase Resistance that has
reduced affinity for trimethoprim and
pyrimethamine.
 transmitted among Gram-negative bacteria
by plasmids.
 ANTI – FUNGAL
DRUGS
 INTRODUCTION
Fungal diseases are those caused by pathogenic fungi, which
are 100 species known to cause mycoses in human.
Human fungi infections can be divided into four
groups:

1. systemic or deep mycoses

2. subcutaneous mycoses
3. cutaneous mycoses
4. superficial mycoses
 Classification of antifungal agents
Synthetic agents
– Acids and their derivatives -Phenolic
derivatives
– Halogen containing compounds - Thiocarbamate
derivatives
– Pyrimimidine derivatives -Acridine
derivatives
– Azole derivatives (imidazole derivatives and
triazole derivatives)
– Allylamine derivatives
Antibiotics: i-Polyenes ii- Nonpolyenes
 I- Acids and derivatives
E.gs.: Fatty acids, benzoic acid, salicylic acid and
triacetin (glyceryl triacetate). Fatty acids like propionic
acid, caprylic
acid, and undecylenic acid.
 II- Pyrimidine derivatives
E.g.: Flucytosine (Ancbon)

5- Fluorocytosine or 5-FC
 Mode of action
Action of flucytosine in fungi.

5-Flucytosine is transported into the

fungal cell, where it is deaminated to
5-fluorouracil (5-FU). The 5-FU is
then converted to 5-fluorouracil-
ribose monophosphate (5-FUMP)
and then is either converted to 5-
FUTP and incorporated into RNA or
converted by ribonucleotide
reductase to 5-FdUMP, which is a
potent inhibitor of thymidylate
synthase.
Uses: 5-FC has narrow spectrum. It is used orally for treatment of
serious systemic infections caused by pathogenic yeasts such as
Candida albicans.
 III- Phenolic derivatives
e. g. Parachlorometaxylenol

Mode of action
Denaturation of protein via the reaction of the acidic phenolic
group with basic centers in the protein molecule located on cell
wall of fungal cell.
Uses: It is used topically in the treatment of tinea infection such
as athlete’s foot
IV- Thiocarbamate V-Halogens and
derivatives halogenophors
E.g. Tolnaftate E.g. Clioquinol

Uses
Treatment of superficial tinea
infections of the skin in the form
of 1% cream, powder, aerosol,
gel, and solution.
Mode of action
Competes with co-enzymes for
metal binding sites on enzymes.
VI- Azole derivatives
Mode of action of azole derivatives:

 All azoles exert antifungal activity by inhibiting Cytochrome P450

enzymes responsible for the demethylation of Lanosterol to
Ergosterol(alpha sterol demethylase). Reduced fungal membrane
Ergosterol concentrations result in damaged, leaky cell membranes.
 1. Clotrimazole

Uses: Clotrimazole is used for the

treatment of topical infections like
tinea, mucocutaneous candidiasis,
and vaginal candidiasis. It is not
used orally for treatment of
systemic infections as it causes
2-Miconazole
Uses
Miconazole base can be used intravenously in
the treatment of systemic fungal infections.
Topically miconazole nitrate can be used in
the treatment of tinea versicolor,
mucocutaneous candidiasis, and of corneal
infection caused by candida and aspergillus.

3- Ketoconazole
Uses
- Topically in treatment of many fungal
infections.
- Orally, it is effective in many
mucocutaneous and systemic mycoses, or
to treat severe cutaneous dermatophytic
infections,which do not respond to topical
therapy or oral griseofulvin.
 Triazole derivatives
 E.g.: Fluconazole

Uses
Fluconazole is taken orally for the treatment of mucocutaneous
and systemic mycoses.
 H- Allylamine derivatives
E.g. Terbinafine

Terbinafine hydrochloride (Lamisil) is a synthetic allylamine

antifungal. It is highly lipophilic in nature and tends to
accumulate in skin, nails, and fatty tissues.
Mode of action
Like other allylamines,
terbinafine inhibits ergosterol
synthesis by inhibiting squalene
epoxidase, an enzyme that is
part of the fungal cell
membrane synthesis pathway.
Because terbinafine prevents
conversion of squalene to
lanosterol, ergosterol cannot be
synthesized. This is thought to
change cell membrane
permeability.
 Antifungal antibiotics
A. Non polyenes
E.g.: Griseofulvin
Mode of action
• Griseofulvin arrests cell division in
metaphase
in vitro. The drug causes a rapid, reversible
dissolution of mitotic spindle apparatus,
apparently by binding with tubulin dimer
required for microtubule assembly.

• Obtention Griseofulvin is isolated from certain strains of

Penicillium griseofulvum or obtained by other means.
Uses
• Griseofulvin is recommended for the systemic treatment of
refractory ringworm infections of the body, nails, hair, and feet
i.e. tinea caused by various species of dermatophytic fungi but
not effective against tinea neither versicolor nor pathogenic
yeasts.
 B- Polyene antifungal antibiotics

They are structurally complex antifungal

antibiotics isolated from soil bacteria containing a
conjugated system of double bonds in large
lactone ring.

They fall into two groupings either 26- membered

ring polyenes such as natamycin, or 38-membered
ring polyenes such as nystatin, amphotericin B,
and candicidin.
 1.Amphotericin B

As the name implies, amphotericin is an amphoteric substance

containing a primary amino group in the sugar moiety and a
carboxyl group attached to the macrolide group.
Intravenously, it is indicated for the treatment of
serious potentially life threatening fungal infections &
leishmaniasis, also it is used topically for treatment
candida albicans.
 A high prevalence of adverse reactions limits the
usefulness of amphotericin B. some forms of
nephrotoxicity in nearly 80% of the patients is the
most important adverse reaction
 2- Nystatin

• It is a valuable agent for the treatment of local and GIT

monilial infections, for the management of cutaneous and
mucocutaneous candidiasis.
3- Candicidin 4- Natamycin
(26-Membered lactone ring)

• Candicidin is used in the Intended for the treatment of fungal

treatment of vaginal conjunctivitis, plepharitis, and
candidiasis in the form of keratitis.
vaginal tablets.
 Mode of action of polyene antibiotics
 They interact with the lipids of fungal cell membranes to build
'tunnels' through the membrane. Once in place, the contents of
the cell are drained away and the cell is killed. As shown from
their structure one half of the structure is made up of double
bonds and is hydrophobic, while the other half contains a series
of hydroxyl groups and is hydrophilic. It is a molecule of
extremes and as such is ideally suited to act on the cell
membrane in the way that it does. Several polyenes molecules
cluster together such that the alkene chains are to the exterior and
interact favorably with the hydrophobic centre of the cell
membrane. The tunnel resulting from this cluster is lined with
the hydroxyl groups and so is hydrophilic, allowing the polar
contents
of the cell to escape.
 In other words, they cause disorganization of the cell membrane
Summary
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