Antifungal agents-Medicinal Chemistry

DR.Narmin Hamaamin Hussen

1. AntifungalDrugs
Lecture2
MedicinalChemistryIV/2
ndSemester/4
thClass
Dr.NarminHamaamin Hussen
2022-2023
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2. AntifungalDrugs
▪Antifungal medicines are used to treat fungal infections, which most commonly affect
your skin, hair and nails.
▪Fungalinfectionscommonlytreatedwithantifungalsinclude:
a.ringworm
b.athlete'sfoot
c.fungalnailinfection
d.vaginalthrush
e.sometypesofseveredandruff
▪Somefungalinfectionscangrowinsidethebodyandneedtobetreatedinhospital.
Examplesinclude:
a.aspergillosis,whichaffectsthelungs
b.fungalmeningitis,whichaffectsthebrain
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3. Typesoffungalinfections
1.Superficial:Affectskin–mucous membrane.
a)Tineaversicolor,Dermatophytes:Fungithataffectkeratinlayerofskin,hair,nail.e.g.tineapedis,ringworm
infection
b)Candidiasis: Yeast-like,oralthrush,vulvovaginitis,nailinfections.
2. Affectinternalorgansas:lung,heart , brainleading topneumonia , endocarditis,meningitis
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4. BiochemicalTargetsforAntifungalChemotherapy
▪Antifungalchemotherapydependson
biochemicaldifferencesbetweenfungi
andmammals
▪Unlikebacteria,whichareprokaryotes,
bothfungiandmammalsareeukaryotes
▪Thefungalcellwall
▪Othertargetsforantifungalagents
includeinhibitorsofDNAbiosynthesis,
▪Sterols
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5. FungalCellWall
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6. Classification of antifungal drugs based on structure
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7. Classificationofantifungaldrugsbasedonmechanismofaction
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8. Antifungalantibiotics
1-Polyeneantibiotics:Nystatin&AmphotericinB
2-Heterocyclic Benzofuran:Griseofulvin
Polyeneantibiotics(polyene=manydouble bonds)
➢Nystatin
▪Nystatinthefirstclinicallyusefulpolyeneantifungalantibiotic,isaconjugatedtetraeneisolatedfromcultures
ofthebacteriumStreptomycesnourseiin1951.
▪ItisusedtotreatCandidainfectionsoftheskinincludingdiaperrash,thrush,esophageal
candidiasis,gastrointestinalcandidiasisandvaginalyeastinfections.
▪Nystatinistootoxictobeusedsystemically,butbecauseverylittledrugisabsorbedfollowingoral
administration,itmaybeadministeredbymouthtotreatfungalinfectionsofthemouthandgastrointestinal
tract
▪Itisasimilarinstructure&mechanismtoamphotericinB
▪Nystatinactsbybindingtosterolsinthecellmembraneofsusceptiblefungiwitharesultantchangein
membranepermeabilityallowingleakageofintracellularcomponents.
▪Nystatinisaneffectivetopicalantifungalagainstawidevarietyoforganismsandisavailableinavarietyof
creamsandointments.
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9. ➢AmphotericinB
▪Itisanamphotericcompoundthatconsistsofseven-conjugateddoublebond,aninternalester,afreecarbonylgroup,anda
glycosidesidechainwithaprimaryaminogroup.
▪ThecarbohydratemoietyisD-mycosamine.Theconjugatedsystemsareusuallyofalltransconfigurations,sothatthering
containsaplannerlipophilicsegmentandalessrigidhydrophilicportion.
▪AmphotericinB,whichasaheptaenehaslowenoughtoxicitytomammaliancellstopermitintravenous(IV)
administration,wasdiscoveredin1956.
▪Thefirstisolatefromthestreptomycetewasaseparablemixtureoftwocompounds,designatedamphotericinsAandB.In
testcultures,compoundBprovedtobemoreactive,andthisistheoneusedclinically.
▪AmphotericinBinjectionisusedtotreatseriousandpotentiallylife-threateningfungalinfections(SystemicFungal
Infections,CryptococcalMeningitis,VisceralLeishmaniasisandblackfungus)
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10. 10
▪AmphotericinBisaverytoxicdrugandmustbeusedwithcaution.
▪Adverseeffectsincludefever,shakingchills,hypotension,andseverekidneytoxicity.
▪MorerecentlydevelopedformulationsofamphotericinB,suchasliposomalencapsulationandlipidcomplexes,have
dramaticallydecreasedthetoxicityofthedrugtohumans,whichpermitshigherplasmalevelstobeemployed.
▪Themechanismsbywhichthenewformulationsdecreasethetoxicityarenotentirelyclear,butaltereddistributionis
clearlyafactor.Becausethebloodvesselsatthesiteofinfectionaremorepermeablethanthoseofnormaltissue,the
largesuspendedparticlesofthelipidformulationscanpenetratethesiteofinfectionmorereadilythantheycan
penetratehealthytissue.Theresultisselectivedeliveryofdrugtothesiteofinfection.
▪SomeevidencealsoindicatesthatthenewerformulationstransferamphotericinBtoergosterol-containingfungalcells
moreefficientlythantocholesterol-containingmammaliancell
▪Thedrugcannotcrosstheblood–brainbarrierandmustbeadministeredintrathecallyfortreatmentoffungal
infectionsoftheCNS.

11. MechanismofAction
▪Thelipophilicpolyeneportioncrossesthecelllipidbilayerformingaporeinthecellmembrane
▪Polyeneshaveademonstrablyhigheraffinityformembranescontainingergosterolovercholesterol-
containingmembranes.Thisisthebasisfortheirgreatertoxicitytofungalcells.
▪AmphotericinBisbelievedtointeractwithmembranesterols(ergosterolinfungi)toproduceanaggregate
thatformsatransmembranechannel.Intermolecularhydrogenbondinginteractionsamonghydroxyl,
carboxyl,andaminogroupsstabilizethechannelinitsopenform,destroyingsymportactivityandallowing
thecytoplasmiccontentstoleakout.Theeffectissimilarwithcholesterol
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12. Whatis'BlackFungus'or'Mucormycosis(Zygomycosis)'?:Symptomsandtreatment
▪Mucormycosis,commonlycalledblackfungus,isaseriousandrarefungalinfection
affectingthosesufferingfromcoronavirusinIndia.
▪Theblackfungusthatinvadesthebrainisbeingincreasinglyseeninvulnerable
patientsinIndiaasthehealthsystemcontinuestostruggleamidthepandemic.
▪Thisinfectioncausedbyagroupoffungicalledmucormycetes.Theseareubiquitous
intheenvironmentandcanoftenbeseenonrottingfood.Despitebeingcommonin
theenvironment,itdoesn’tcauseinfectioninhumansasourimmunecellscaneasily
fightsuchpathogens.
▪MucormycosisisadeadlyfungalinfectionfoundinsomeCovid-19patientswith
uncontrolleddiabetesandprolongedintensivecareunit(ICU)stay
▪InCOVID-19patientswithdiabetesandimmuno-suppressedindividuals,onemust
suspectmucormycosisifthereissinusitis,one-sidefacialpainornumbness,blackish
discolourationoverthebridgeofthenoseorpalate,toothache,blurredordouble
visionwithpain,skinlesion,thrombosis,chestpainandworseningrespiratory
symptoms,itsaid
▪Medicaltreatment(AmphotericinBinfusionandanti-fungaltherapyforatleastsix
weeks)
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13. HeterocyclicBenzofuran:
➢Griseofulvin
▪GriseofulvinisanantifungalantibioticproducedbyanunusualstrainofPenicillium.
▪Griseofulvinisanantifungalmedicationusedtotreatanumberoftypesofdermatophytoses
(ringworm).Itisusedorallytotreatsuperficialfungalinfections,primarilyfingernail,toenailand
scalpinfections,butitdoesnotpenetrateskinornailsifusedtopically.
▪Themechanismofactionofgriseofulvinisthroughbindingtotheproteintubulin,whichinterferes
withthefunctionofthemitoticspindleand,thereby,inhibitscelldivision.Griseofulvinalsomay
interferedirectlywithDNAreplication.
▪Griseofulvinisabsorbedbestwhenitistakenwithahighfatmeal,suchasacheeseburger,whole
milk,oricecream.
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14. AntifungalAzoles
▪AntifungalAzolesaresyntheticdrugswithbroad-spectrumfungistaticactivity.Azolescanbedividedintotwo
groups:
➢Azole-imidazoleagents(clotrimazole,ketoconazole,miconazole)inwhichthefive-memberazolenucleus
containstwonitrogens
➢Newerazole-triazolecompounds(fluconazole,itraconazole,andvoriconazole),inwhichtheazolenucleus
containsthreenitrogens.
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15. Mechanismofaction
▪Alltheazolesactbyinhibitingergosterolbiosynthesisthrough
inhibition14a-demethylase,CYP50.
▪AzolesexertantifungalactivitybyinhibitingcytochromeP450
enzymesresponsibleforthedemethylationoflanosterolto
ergosterol. Reducedfungalmembraneergosterol
concentrationsresultindamaged,leakycellmembranes.
▪Thetoxicityofthesedrugsdependsontheirrelativeaffinities
formammalianandfungalcytochromeP450enzymes.The
triazolestendtohavefewersideeffects,betterabsorption,
betterdrugdistributioninbodytissues,andfewerdrug
interactions.
▪ThebasicN3atomoftheazoleformsabondwiththeheme
ironoftheCYP450prostheticgroupinthepositionnormally
occupiedbytheactivatedoxygen.Theremainderoftheazole
antifungalformsbondinginteractionswiththeapoproteinina
mannerthatdeterminestherelativeselectivityofthedrugfor
thefungaldemethylaseversusotherCYP450enzymes
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16. 1.Thebasicstructuralrequirementformembersoftheazoleclassisa
weaklybasicimidazoleor1,2,4-triazolering(pKaof6.5–6.8)bonded
byanitrogen–carbonlinkagetotherestofthestructure.
2.Atthemolecularlevel,theamidinenitrogenatom(N-3inthe
imidazoles,N-4inthetriazoles)isbelievedtobindtothehemeiron
ofenzyme-boundcytochromeP450toinhibitactivationofmolecular
oxygenandpreventoxidationofsteroidalsubstratesbytheenzyme.
3.3.Themostpotentantifungalazolespossesstwoorthreearomatic
rings,atleastoneofwhichishalogensubstituted(e.g.,2,4-
dichlorophenyl,4-chlorophenyl,2,4-difluorophenyl),andother
nonpolarfunctionalgroups.
4.Only2,and/or2,4substitutionyieldseffectiveazolecompounds.
5.Thehalogenatomthatyieldsthemostpotentcompoundsis
fluorine,althoughfunctionalgroupssuchassulfonicacidshavebeen
showntodothesame.
6.Substitutionatotherpositionsoftheringyieldsinactive
compounds.
7.Presumably,thelargenonpolarportionofthesemoleculesmimics
thenonpolarsteroidalpartofthesubstrateforlanosterol14-
demethylase,lanosterol,inshapeandsize.
8.Thenonpolarfunctionalityconfershighlipophilicitytothe
antifungalazoles.
9.Thefreebasesaretypicallyinsolubleinwaterbutaresolublein
mostorganicsolvents,suchasethanol.
10..Fluconazole,whichpossessestwopolartriazolemoieties,isan
exception,inthatitissufficientlywatersolubletobeinjected
intravenouslyasasolutionofthefreebase
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17. Imidazoleantifungalagents
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18. ➢Ketoconazole
▪Ketoconazole,animidazoleantifungal,wasthefirstorallyactiveantifungalazoletobediscoveredand,asa
consequence,hasbeenwidelystudiedandemployedforthetreatmentofsystemicfungalinfections,primarily
candidiasis.KetoconazolehaslittleeffectonAspergillusorCryptococcus.
▪Ketoconazoleisahighlylipophiliccompound.Thispropertyleadstohighconcentrationsofketoconazoleinfatty
tissuesandpurulentexudates.
▪KetoconazoleishighlydependentonlowstomachpHforabsorption,andantacidsordrugsthatraisestomach
pHwilllowerthebioavailabilityofketoconazole.
▪EvidencethatCYP3A4playsasignificantroleinmetabolismofketoconazoleisthatcoadministrationofCYP3A4
inducers,suchasphenytoin,carbamazepine,andrifampin,cancauseasmuchasa50%reductioninlevelsof
ketoconazole
▪KetoconazolealsoisapowerfulinhibitorofhumanCYP3A4and,asaconsequence,hasmanyserious
interactionswithotherdrugs.Forexample,coadministrationofketoconazolewiththehypnotictriazolam
resultsina22-foldincreaseintriazolam’sareaunderthecurve(AUC)andasevenfoldincreaseinhalf-life.
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19. Azole-Triazolecompounds
➢Fluconazole
▪Fluconazoledoesnotrequireanacidicenvironment,asdoesketoconazole,forGIabsorption.About80to90%ofanorally
administereddoseisabsorbed,yieldinghighserumdruglevels.Thet1/2ofthedrugis27to37h,permittingonce-daily
dosinginpatientswithnormalrenalfunction.
▪Thedrugpenetrateswidelyintomostbodytissues.Cerebrospinalfluidlevelsare60to80%ofserumlevels,permitting
effectivetreatmentforfungalmeningitis.
▪Fluconazole,whichwasintroducedatthesametimeasitraconazole,differsfromketoconazoleanditraconazoleinthatitis
equallybioavailablewhengivenorallyorIV.
▪Twomajoradvantagesoffluconazoleoverotherantifungalagentsarethatitcancrosstheblood–brainbarrierandhas
efficacyagainstCryptococcusneoformans.FluconazolealsodiffersinthatitisonlyaweakinhibitorofCYP3A4buta
stronginhibitorofCYP2C9.
▪FluconazoleisveryeffectiveinthetreatmentofinfectionswithmostCandidaspp.Thrushintheend-stageAIDSpatient,
oftenrefractorytonystatin,clotrimazole,andketoconazole,canusuallybesuppressedwithoralfluconazole.AIDSpatients
withesophagealcandidiasisalsousuallyrespondtofluconazole.Asingle150mgdosehasbeenshowntobeaneffective
treatmentforvaginalcandidiasis.A3-daycourseoforalfluconazoleisaneffectivetreatmentforCandidaurinarytract
infection.Stablenon-neutropenicpatientswithcandidemiacanbeadequatelytreatedwithfluconazole
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20. ➢Voriconazole
▪Voriconazoleisafluconazoleanalogthatwasdevelopedtoovercomesomeof
thelimitationsoffluconazoleanddoes,indeed,haveabroaderspectrumof
activitythanfluconazole,havingactivityagainstAspergillusandfluconazole-
resistantstrainsofCandidaandCryptococcus.
▪Voriconazoleisorallyabsorbedandpenetratestheblood–brainbarrier.
Unfortunately,voriconazoleisextensivelymetabolizedCYP450enzymesandis
aninhibitorofCYP2C19,CYP2C9,andCYP3A4,leadingtomanydrug
interactions
➢Posaconazole
▪Posaconazole,arecentlyintroducedtriazole,hasanumberofadvantages
overpreviousagents.Posaconazolehasawidespectrumofactivity
comparedtootherazoles,particularlyagainstAspergillusandother
increasinglycommonnosocomialinfectionsresistanttotreatmentby
otherantifungaldrugs.
▪Posaconazoleisstructurallysimilartoitraconazoleandsaperconazole,
butitcontainsatetrahydrofuranringinplaceofthedioxolanringof
thoseagents,whichmayaccountforsomeofitsuniqueproperties.
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21. AllylaminesandOtherSqualeneEpoxidaseInhibitors
➢Terbinafine,TolnaftateandNaftifine
▪Thegroupofagentsgenerallyknownasallylaminesstrictlyincludesonlynaftifineandterbinafine,but
becausebutenafineandtolnaftatefunctionbythesamemechanismofaction,theyareincludedinthis
class.
▪Allylaminesreversiblenoncompetitive
ofthefungalenzymesqualeneinhibitors
epoxidase,
lanosterol.
which
Witha
convertssqualeneto
decreaseinlanosterol
ergosterolproductionisalsoproduction,
diminished,affectingfungalcellmembrane
synthesisandfunction.Theseagentsexhibit
fungicidalactivityagainstdermatophytesand
fungistaticactivityagainstyeasts.Squalene
epoxidaseformsanepoxideattheC2–C3
studiesintheseries
positionofsqualene
▪Structure–activity
subsequentlyledtothediscoveryof
compoundswithenhancedpotencyand
potentialoral activity,suchasterbinafine.
X
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22. ➢Terbinafine
▪Terbinafineisavailableinbothtopicalandoraldosageformsandiseffectiveagainsta
varietyofdermatophyticinfectionswhenemployedtopicallyorsystemically.Aunique
▪propertyofterbinafineisitseffectivenessinthetreatmentofonychomycoses(nail
infections).
▪Givenorally,thehighlylipophilicdrugredistributesfromtheplasmaintothenailbedand
intothenailitself,wheretheinfectionresides,makingterbinafinesuperiortoother
agentsfortreatingthisparticulartypeofinfection.
➢Naftifine
▪Naftifinewasthefirstallylaminetobediscoveredandmarketed.Becauseofitsextensivefirst-pass
metabolism,naftifineisnotusedorallyandisonlyavailableintopicalpreparations.
▪Thewidestuseofnaftifineisagainstvarioustineainfectionsoftheskin.
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23. InhibitorsofCellWallBiosynthesis(inhibitionoftheenzymeβ-1,3-glucansynthase)
➢Echinocandins
▪Echinocandins,agroupofcyclicpeptideswithlonglipophilicsidechainsand
sometimescalledlipopeptides,havebeenunderinvestigationforanumber
ofyears.
▪Echinocandinsinterferewithcellwallbiosynthesisthroughinhibitionofthe
enzymeβ-1,3-glucansynthase.
▪β-Glucanisanimportantpolymercomponentofmanyfungalcellwalls,and
reductionintheglucancontentseverelyweakensthecellwall,leadingto
ruptureofthefungalcell.
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24. ➢Caspofungin
▪Caspofunginisasemisyntheticlipopeptide.Itinhibitsthesynthesisofbeta-D-glucan,acellwallcomponentof
filamentousfungi.
▪Caspofunginisapprovedforthetreatmentofinvasiveaspergillosisinpatientsnotrespondingtoamphotericin
B,anditraconazole.
▪Adverseeffectsaremediatedthroughhistaminerelease:facialflushing,rash,fever,andpruritus.Dose
reductionsarerequiredinthepresenceof moderatehepaticinsufficiency.
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25. Fluorinatedpyrimidines
➢Flucytosine
▪Flucytosine(5-flucytosine,5-FC)isananalogueofcytosinethatwasoriginallysynthesizedforpossibleuseas
anantineoplasticagent
▪Flucytosineisapowerfulantifungalagentusedinthetreatmentofserioussystemicfungalinfections,suchas
CryptococcusneoformansandCandidaspp
▪Flucytosineitselfisnotcytotoxicbut,rather,isaprodrugthatistakenupbyfungiandmetabolizedto5-fl
uorouracil(5-FU)byfungalcytidinedeaminase.Then,5-FUisconvertedto5-fluorodeoxyuridine,whichisa
thymidylatesynthaseinhibitorthatinterfereswithbothproteinandRNAbiosynthesis.5-Fluorouracilis
cytotoxicandisemployedincancerchemotherapy
▪Humancellsdonotcontaincytosinedeaminaseand,therefore,donotconvertflucytosineto5-FU.Some
intestinalflora,however,doconvertthedrugto5-FU,sohumantoxicitydoesresultfromthismetabolism.
▪Resistancerapidlydevelopstoflucytosinewhenusedalone,soitisalmostalwaysusedinconjunctionwith
amphotericinB.Useofflucytosinehasdeclinedsincethediscoveryoffluconazole
Flucytosine,aprodrug,isconvertedbyfungalcytosinedeaminaseto5-fluorouracil(5-FU).Thisreactiondoesnotoccurinmammaliancells.Afurther
transformationof5-FUtotheactualcytotoxicagent5-fluorodeoxyuridinemonophosphate(5-FdUMP)alsooccur
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26. ✓What is liposomal encapsulation? How does
liposome drug delivery work?
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27. Thank You
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