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ANTIFUNGAL DRUGS
1
3
Mr.Ganesh D.Mote
Monera is a kingdom that contains 
unicellular organisms with a 
prokaryotic cell organization, (having 
no nuclear membra...
3
THE FUNGI KINGDOM
Mycology - the study of fungi
fungi - singular
fungus - plural
1) fungi are eukaryotic
•they have a nu...
4
Major Types of 
Mycoses
superficial
cutaneous
subcutaneous
systemic
opportunistic
1. OVER VIEW OF FUNGAL INFECTION...
PATHOGENIC FUNGAI
1. CANDIDA
2. ASPERGILLUS
3. CRYPTOCOCCUS
4. HISTOPLASMA
5. PNEUMOCYSTIS
6. STACHYBOTRYS
7. MICROSPORUM
...
1). CANDIDA
Candida species cause infections in
individuals with deficient immune
systems. Th1-type cell-mediated
immunity...
7
2). ASPERGILLUS
•The most common pathogenic species are Aspergillus fumigatus and
Aspergillus flavus. Aspergillus flavus...
8
2. TYPES OF FUNGAL INFECTIONS 
9
Aspergillus
fumigatus Infection
Aspergillus flavus
Infection
2. TYPES OF FUNGAL INFECTIONS 
Mr.Ganesh D.Mote
10
3. CRYPTOCOCCUS
•Cryptococcus neoformans can cause  a  severe  form  of  meningitis 
and meningo-encephalitis in patien...
11 CRYPTOCOCCUS  INFECTION
2. TYPES OF FUNGAL INFECTIONS
Mr.Ganesh D.Mote
12
CRYPTOCOCCUS INFECTIONS
2. TYPES OF FUNGAL INFECTIONS
Mr.Ganesh D.Mote
4. HISTOPLASMA
Histoplasma capsulatum can cause
histoplasmosis in humans, dogs and
cats.
Infection is usually due to inhal...
14
2. TYPES OF FUNGAL INFECTIONS
HISTOPLASMA INFECTIONSMr.Ganesh D.Mote
15
5. PNEUMOCYSTIS
Pneumocystis jirovecii
(or Pneumocystis carinii) can
cause a form of pneumonia
in people with weakened
...
16
2. TYPES OF FUNGAL INFECTIONS
PNEUMOCYSTISMr.Ganesh D.Mote
6. STACHYBOTRYS
Stachybotrys chartarum or "black mold"
can cause respiratory damage and
severe headaches. It frequently oc...
18
7. MICROSPORUM
Microsporum canis is
a fungus that can
cause tinea capitis in
humans, and
simple ringworm in pets.
2. TY...
MICROSPORUM CANIS INFECTION
2. TYPES OF FUNGAL INFECTIONS
19
Mr.Ganesh D.Mote
20
The fungus genus Trichophyto
n rubrum is characterized by
the development of both
smooth-walled macro-
and microconidia...
2. TYPES OF FUNGAL INFECTIONS
TRICHOPHYTON INFECTION
21
22
5.CLASSIFICATION
Mr.Ganesh D.Mote
Chemical classification with structure
Mr.Ganesh D.Mote23
1.Antifunal antibiotics
a.Polyene antibiotics
b.Other antifungal...
2.Allyl amines
Mr.Ganesh D.Mote24
terbinafine
Tolnaftate
25
3. CHEMICAL STRUCTURES AZOLE ANTIFUNGAL DRUGS
Mr.Ganesh D.Mote
5.CLASSIFICATION OF ANTIFUNGAL
Con…
26
Mr.Ganesh D.Mote
27
6.SITES OF ACTION OF COMMON ANTIFUNGAL DRUGS
Con…
POLYENES
IMIDAZOLES
TRIAZOLE
ALLYLAMINES
OTHER
GLUCAN
SYNTHASE
INHIBI...
6.SITES OF ACTION OF COMMON ANTIFUNGAL DRUGS
ALLYLAMINES
IMIDAZOLES
TRIAZOLE
POLYENES
28
GLUCAN
SYNTHASE
INHIBITORS
29
6.SITES OF ACTION OF COMMON ANTIFUNGAL DRUGS
Mr.Ganesh D.Mote
FLUCYTOSINE
IMIDAZOLES
TRIAZOLES
POLYENES
CANDINS
GRISEOFULVIN
OTHERS
30
7. ANTI FUNGAL DRUGS MECHANISAM
Mr.Ganesh D.Mote
31
8.MECHANISM OF AMPHOTERICIN B
Several amphotericin B molecules
bind to ergosterol in the plasma
membranes of sensitive ...
Flucytosine enters fungal cells via a
cytosine-specific permease an enzyme not
found in mammalian cells.
Flucytosine is th...
10.MECHANISM OF KETOCONAZOLE
Azoles are predominantly fungistatic.
They inhibit C-14 α-demethylase (a
cytochrome P450 enzy...
Terbinafine inhibits fungal
squalene epoxidase, thereby
decreasing the synthesis of
ergosterol .
This plus the accumulatio...
35
It is only fungistatic, and it causes a
number of significant drug
interactions.
Griseofulvin accumulates in newly
synt...
36
13. SOME ADVERSE REACTIONS OF ANTIFUNGAL DRUGS
Mr.Ganesh D.Mote
37
14. SOME ADVERSE REACTIONS OF AMPHOTERICIN B.
Mr.Ganesh D.Mote
38
POLYENES
Mr.Ganesh D.Mote
39
IMIDAZOLES
Mr.Ganesh D.Mote
40
TRIAZOLE ALLYLAMINES
Mr.Ganesh D.Mote
41
Β-3-GLUCAN SYNTHASE
INHIBITORS
Mr.Ganesh D.Mote
42
Griseofulvin Flucytosine
Dr.K.Saminathan.M.Pharm, M.B.A, Ph.D
Mr.Ganesh D.Mote
SAR OF AZOLE ANTIFUNGAL AGENTS
1. The basic structural requirement for members of the azole class is a weakly basic
imidaz...
Mechanism action of squaline epoxidase(allyl
amines and lanoseterol 14 ά demethylase
inhibitor(Azoles derivatives)
Mr.Gane...
Synthesis of Ketoconazole
45
Cl
Cl
C
O
CH2Br
2-bromo-1-(2,4-dichlorophenyl)ethanone
CH2OH
HC
H2C OH
OH
propane-1,2,3-triol...
Mr.Ganesh D.Mote46
1-(3,4-dichlorophenyl)-2-(1H-
imidazol-1-yl)ethanone
Cl C
O
H2
C N
Cl
N
Cl C
H
OH
H2
C N
Cl
N
1-(3,4-di...
Mr.Ganesh D.Mote47
2-Naphthol thiophosgene
N-methyl 3-toludine
O
Cl
S
O-naphthalen-2-yl carbonochloridothioate
O
N
S
CH3
C...
Thank you
Mr.Ganesh D.Mote48
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Medicinal chemistry of Antifungal agents

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Introduction of pathogenic Fungi,Chemical Classification of antifungal agents,SAR and structure of antifungal agents and Synthesis of Antifungal drugs

Published in: Health & Medicine

Medicinal chemistry of Antifungal agents

  1. 1. ANTIFUNGAL DRUGS 1 3 Mr.Ganesh D.Mote
  2. 2. Monera is a kingdom that contains  unicellular organisms with a  prokaryotic cell organization, (having  no nuclear membrane), such as  bacteria eukaryotic one-celled  living organisms  distinct from  multicellular plants  and animals: protozoa,  slime molds, and  eukaryotic algae taxonomic kingdom  comprising all living  or extinct animals Plants, also called green plants (Viridiplantae  in Latin), are living multicellular  organisms of thekingdom Plantae. 1. OVER VIEW OF FUNGAL Lack chlorophyll, leaves, true stems, and  roots, reproduce by spores, and live as  saprotrophs or parasites 2 Mr.Ganesh D.Mote
  3. 3. 3 THE FUNGI KINGDOM Mycology - the study of fungi fungi - singular fungus - plural 1) fungi are eukaryotic •they have a nuclei & mitochondria 2) they are heterotrophs •they depend on other organisms for food 3) they are multicellular 4) they cannot move on their own 4 Main Characteristics of Fungi 1. OVER VIEW OF FUNGAL Mr.Ganesh D.Mote
  4. 4. 4 Major Types of  Mycoses superficial cutaneous subcutaneous systemic opportunistic 1. OVER VIEW OF FUNGAL INFECTION Mr.Ganesh D.Mote
  5. 5. PATHOGENIC FUNGAI 1. CANDIDA 2. ASPERGILLUS 3. CRYPTOCOCCUS 4. HISTOPLASMA 5. PNEUMOCYSTIS 6. STACHYBOTRYS 7. MICROSPORUM 8. TRICHOPHYTON 5 2. TYPES OF FUNGAL INFECTIONS  Mr.Ganesh D.Mote
  6. 6. 1). CANDIDA Candida species cause infections in individuals with deficient immune systems. Th1-type cell-mediated immunity (CMI) is required for clearance of a fungal infection. 6 2. TYPES OF FUNGAL INFECTIONS  CANDIDA INFEC TIONS
  7. 7. 7 2). ASPERGILLUS •The most common pathogenic species are Aspergillus fumigatus and Aspergillus flavus. Aspergillus flavus produces aflatoxin which is both a toxin and a carcinogen and which can potentially contaminate foods such as nuts. •Aspergillus fumigatus and Aspergillus clavatus can cause allergic  disease.  •Some Aspergillus species cause disease on grain crops,especially maize,and synthesize mycotoxins including aflatoxin. •Aspergillosis is the group  of  diseases  caused  by  Aspergillus.  The symptoms include fever,  cough,  chest  pain  or  breathlessness. Usually, only patients with weakened immune systems or with other lung conditions are susceptible. 2. TYPES OF FUNGAL INFECTIONS  Mr.Ganesh D.Mote
  8. 8. 8 2. TYPES OF FUNGAL INFECTIONS 
  9. 9. 9 Aspergillus fumigatus Infection Aspergillus flavus Infection 2. TYPES OF FUNGAL INFECTIONS  Mr.Ganesh D.Mote
  10. 10. 10 3. CRYPTOCOCCUS •Cryptococcus neoformans can cause  a  severe  form  of  meningitis  and meningo-encephalitis in patients with HIV infection and AIDS. The majority of Cryptococcus species live in the soil and do not cause disease in humans. • Cryptococcus neoformans is the major human and animal pathogen. Cryptococcus laurentii and Cryptococcus albidus have been known to occasionally cause moderate-to-severe disease in human patients with compromised immunity. •Cryptococcus gattii is endemic to tropical parts of the continent of Africa and Australia and can cause disease in non- immunocompromised people. 2. TYPES OF FUNGAL INFECTIONS Mr.Ganesh D.Mote
  11. 11. 11 CRYPTOCOCCUS  INFECTION 2. TYPES OF FUNGAL INFECTIONS Mr.Ganesh D.Mote
  12. 12. 12 CRYPTOCOCCUS INFECTIONS 2. TYPES OF FUNGAL INFECTIONS Mr.Ganesh D.Mote
  13. 13. 4. HISTOPLASMA Histoplasma capsulatum can cause histoplasmosis in humans, dogs and cats. Infection is usually due to inhaling contaminated air. 2. TYPES OF FUNGAL INFECTIONS 13 Mr.Ganesh D.Mote
  14. 14. 14 2. TYPES OF FUNGAL INFECTIONS HISTOPLASMA INFECTIONSMr.Ganesh D.Mote
  15. 15. 15 5. PNEUMOCYSTIS Pneumocystis jirovecii (or Pneumocystis carinii) can cause a form of pneumonia in people with weakened immune systems, such as premature children, the elderly, and AIDS patients. 2. TYPES OF FUNGAL INFECTIONS Mr.Ganesh D.Mote
  16. 16. 16 2. TYPES OF FUNGAL INFECTIONS PNEUMOCYSTISMr.Ganesh D.Mote
  17. 17. 6. STACHYBOTRYS Stachybotrys chartarum or "black mold" can cause respiratory damage and severe headaches. It frequently occurs in houses in regions that are chronically damp. 2. TYPES OF FUNGAL INFECTIONS 17 Mr.Ganesh D.Mote
  18. 18. 18 7. MICROSPORUM Microsporum canis is a fungus that can cause tinea capitis in humans, and simple ringworm in pets. 2. TYPES OF FUNGAL INFECTIONS Mr.Ganesh D.Mote
  19. 19. MICROSPORUM CANIS INFECTION 2. TYPES OF FUNGAL INFECTIONS 19 Mr.Ganesh D.Mote
  20. 20. 20 The fungus genus Trichophyto n rubrum is characterized by the development of both smooth-walled macro- and microconidia. Macroconidiaare mostly borne laterally directly on the hyphae or on short pedicels, and are thin- or thick- walled, clavate to fusiform, and range from 4 to 8 by 8 to 50 μm in size 8. TRICHOPHYTON 2. TYPES OF FUNGAL INFECTIONS Mr.Ganesh D.Mote
  21. 21. 2. TYPES OF FUNGAL INFECTIONS TRICHOPHYTON INFECTION 21
  22. 22. 22 5.CLASSIFICATION Mr.Ganesh D.Mote
  23. 23. Chemical classification with structure Mr.Ganesh D.Mote23 1.Antifunal antibiotics a.Polyene antibiotics b.Other antifungal antibiotics griseofulvin
  24. 24. 2.Allyl amines Mr.Ganesh D.Mote24 terbinafine Tolnaftate
  25. 25. 25 3. CHEMICAL STRUCTURES AZOLE ANTIFUNGAL DRUGS Mr.Ganesh D.Mote
  26. 26. 5.CLASSIFICATION OF ANTIFUNGAL Con… 26 Mr.Ganesh D.Mote
  27. 27. 27 6.SITES OF ACTION OF COMMON ANTIFUNGAL DRUGS Con… POLYENES IMIDAZOLES TRIAZOLE ALLYLAMINES OTHER GLUCAN SYNTHASE INHIBITORS BIND TO ERGOSTEROL AND FORM PORES (CHANNELS) Mr.Ganesh D.Mote
  28. 28. 6.SITES OF ACTION OF COMMON ANTIFUNGAL DRUGS ALLYLAMINES IMIDAZOLES TRIAZOLE POLYENES 28 GLUCAN SYNTHASE INHIBITORS
  29. 29. 29 6.SITES OF ACTION OF COMMON ANTIFUNGAL DRUGS Mr.Ganesh D.Mote
  30. 30. FLUCYTOSINE IMIDAZOLES TRIAZOLES POLYENES CANDINS GRISEOFULVIN OTHERS 30 7. ANTI FUNGAL DRUGS MECHANISAM Mr.Ganesh D.Mote
  31. 31. 31 8.MECHANISM OF AMPHOTERICIN B Several amphotericin B molecules bind to ergosterol in the plasma membranes of sensitive fungal cells. There, they form pores (channels) that require hydrophobic interactions between the lipophilic segment of the polyene antibiotic and the sterol. The pores disrupt membrane function, allowing electrolytes (particularly potassium) and small molecules to leak from the cell, resulting in cell death. Mr.Ganesh D.Mote
  32. 32. Flucytosine enters fungal cells via a cytosine-specific permease an enzyme not found in mammalian cells. Flucytosine is then converted by a series of steps to 5-fluorodeoxyuridine 5'- monophosphate. This false nucleotide inhibits thymidylate synthase, thus depriving the organism of thymidylic acid an essential DNA component. Note: [Amphotericin B increases cell permeability, allowing more 5-FC to penetrate the cell. Thus, 5-FC and amphotericin B are synergistic.] 9.MECHANISM OF FLUCYTOSINE 32 Mr.Ganesh D.Mote
  33. 33. 10.MECHANISM OF KETOCONAZOLE Azoles are predominantly fungistatic. They inhibit C-14 α-demethylase (a cytochrome P450 enzyme), thus blocking the demethylation of lanosterol to ergosterol the principal sterol of fungal membranes. This inhibition disrupts membrane structure and function and, thereby, inhibits fungal cell growth. [Note:In addition to blocking fungal ergosterol synthesis, the drug also inhibits human gonadal and adrenal steroid synthesis, leading to decreased testosterone and cortisol production. In addition, ketoconazole inhibits cytochrome P450] 33 Dr.K.Saminathan.M.Pharm, M.B.A, Ph.D Mr.Ganesh D.Mote
  34. 34. Terbinafine inhibits fungal squalene epoxidase, thereby decreasing the synthesis of ergosterol . This plus the accumulation of toxic amounts of squalene result in the death of the fungal cell. 11.MECHANISM OF TERBINAFINE 34 Mr.Ganesh D.Mote
  35. 35. 35 It is only fungistatic, and it causes a number of significant drug interactions. Griseofulvin accumulates in newly synthesized, keratin-containing tissue, where it causes disruption of the mitotic spindle and inhibition of fungal mitosis . 12. MECHANISM OF GRISEOFULVIN Mr.Ganesh D.Mote
  36. 36. 36 13. SOME ADVERSE REACTIONS OF ANTIFUNGAL DRUGS Mr.Ganesh D.Mote
  37. 37. 37 14. SOME ADVERSE REACTIONS OF AMPHOTERICIN B. Mr.Ganesh D.Mote
  38. 38. 38 POLYENES Mr.Ganesh D.Mote
  39. 39. 39 IMIDAZOLES Mr.Ganesh D.Mote
  40. 40. 40 TRIAZOLE ALLYLAMINES Mr.Ganesh D.Mote
  41. 41. 41 Β-3-GLUCAN SYNTHASE INHIBITORS Mr.Ganesh D.Mote
  42. 42. 42 Griseofulvin Flucytosine Dr.K.Saminathan.M.Pharm, M.B.A, Ph.D Mr.Ganesh D.Mote
  43. 43. SAR OF AZOLE ANTIFUNGAL AGENTS 1. The basic structural requirement for members of the azole class is a weakly basic imidazole or 1,2,4-triazole ring (pKaof 6.5–6.8) bonded by a nitrogen–carbon linkage to the rest of the structure. 2. At the molecular level, the amidine nitrogen atom (N-3 in the imidazoles, N-4 in the triazoles) is believed to bind to the heme iron of enzyme-bound cytochrome P450 to inhibit activation of molecular oxygen and prevent oxidation of steroidal substrates by the enzyme. 3. The most potent antifungal azoles possess two or three aromatic rings, at least one of which is halogen substituted (e.g., 2,4-dichlorophenyl, 4-chlorophenyl, 2,4-difluorophenyl), and other nonpolar functional groups. 4. Only 2, and/or 2,4 substitution yields effective azole compounds. 5. The halogen atom that yields the most potent compounds is fluorine, although functional groups such as sulfonic acids have been shown to do the same. 6. Substitution at other positions of the ring yields inactive compounds. 7. Presumably, the large nonpolar portion of these molecules mimics the nonpolar steroidal part of the substrate for lanosterol 14-demethylase, lanosterol, in shape and size. 8. The nonpolar functionality confers high lipophilicity to the antifungal azoles. 9. The free bases are typically insoluble in water but are soluble in most organic solvents, such as ethanol. 10.Fluconazole, which possesses two polar triazole moieties, is an exception, in that it is sufficiently water soluble to be injected intravenously as a solution of the free base. 43 Clotrimazole Fluconazole
  44. 44. Mechanism action of squaline epoxidase(allyl amines and lanoseterol 14 ά demethylase inhibitor(Azoles derivatives) Mr.Ganesh D.Mote44
  45. 45. Synthesis of Ketoconazole 45 Cl Cl C O CH2Br 2-bromo-1-(2,4-dichlorophenyl)ethanone CH2OH HC H2C OH OH propane-1,2,3-triol Cl Cl C CH2Br O O CH2OH (2-(bromomethyl)-2-(2,4- dichlorophenyl)-1,3-dioxolan-4- yl)methanol C O Cl Cl Cl C O O CH2COO C H2 N N Cl Cl C O O C H2 N N H2 C O SO2CH3 CH3SO3Cl
  46. 46. Mr.Ganesh D.Mote46 1-(3,4-dichlorophenyl)-2-(1H- imidazol-1-yl)ethanone Cl C O H2 C N Cl N Cl C H OH H2 C N Cl N 1-(3,4-dichlorophenyl)-2-(1H-imidazol-1-yl)ethanol NaBH4 Cl Cl H2 CBr 1-(bromomethyl)-2,4-dichlorobenzene Synthesis of Miconazole
  47. 47. Mr.Ganesh D.Mote47 2-Naphthol thiophosgene N-methyl 3-toludine O Cl S O-naphthalen-2-yl carbonochloridothioate O N S CH3 CH3 O-naphthalen-2-yl methyl(m-tolyl)carbamothioate Synthesis of Tolnaftate
  48. 48. Thank you Mr.Ganesh D.Mote48

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