The biology and chemistry of antifungal agents: A review

21 Pages·2012·0.65 MB·English

by  Muthu K Kathiravan

Bioorganic&MedicinalChemistry20(2012)5678–5698
ContentslistsavailableatSciVerseScienceDirect
Bioorganic & Medicinal Chemistry
journal homepage: www.elsevier.com/locate/bmc
Review
The biology and chemistry of antifungal agents: A review
Muthu K Kathiravana,⇑, Amol B Salakeb, Aparna S Chotheb, Prashik B Dudhea, Rahul P Watodea,
Maheshwar S Muktaa, Sandeep Gadhwea
aSinhgadCollegeofPharmacy,DepartmentofPharmaceuticalChemistry,Vadgaon(Bk),Pune410041,India
bAISSMSCollegeofPharmacy,DepartmentofPharmaceuticalChemistry,KennedyRoad,NearRTO,Shivajinagar,Pune411001,India
a r t i c l e i n f o a b s t r a c t
Articlehistory: Inrecentyearstheirhasbeenanincreaseduseofantifungalagentsandhasresultedinthedevelopment
Received4March2012 ofresistancetodrugs.Currently,useofstandardantifungaltherapiescanbelimitedbecauseoftoxicity,
Revised21April2012 lowefficacyrates.Differenttypesofmechanismscontributetothedevelopmentofresistancetoantifun-
Accepted21April2012
gals.Thishasgivenraisetosearchforanewheterocyclewithdistinctactionormultitargetedcombina-
Availableonline9May2012
tiontherapy.Thisreviewaddressestheareassuchastheunderlyingmechanisms,eightdifferenttargets
suchasergosterolsynthesis,chitinsynthesis,ergosteroldisruptors,glucansynthesis,squaleneepoxidase,
Keywords:
nucleic acidsynthesis,protein synthesis,microtubules synthesis. The clinicallyemployed drugs along
Antifungalagents
withthecurrentresearchworkgoingonworldwideondifferentheterocyclesarediscussed.Inrecent
Heterocyclesazoles
advancesvariousheterocyclesincludingimidazole,benzimidazoleetc.,twentythreescaffoldsandtheir
Imidazoles
leadidentificationarediscussed.
!2012ElsevierLtd.Allrightsreserved.
Contents
1. Introduction........................................................................................................ 5679
1.1. Candidaalbicans................................................................................................ 5679
1.2. Aspergillusniger................................................................................................ 5680
2. Targetsforantifungaltherapy.......................................................................................... 5680
2.1. Fungalergosterolsynthesisinhibitors.............................................................................. 5680
2.1.1. Azoles ................................................................................................ 5680
2.1.2. Ketoconazole........................................................................................... 5681
2.1.3. Itraconazole............................................................................................ 5681
2.1.4. Fluconazole............................................................................................ 5681
2.1.5. Voriconazole........................................................................................... 5682
2.1.6. Posoconazole........................................................................................... 5682
2.1.7. Ravuconazole .......................................................................................... 5682
2.2. Squaleneepoxidaseinhibitors:morpholinesandallylamines........................................................... 5682
2.2.1. Morpholines ........................................................................................... 5682
2.2.2. Amorolfine ............................................................................................ 5682
2.2.3. Terbinafine ............................................................................................ 5682
2.3. Ergosteroldisruptors(polyenesantibiotics) ......................................................................... 5682
2.3.1. AmphotericinB......................................................................................... 5682
2.3.2. Nystatin............................................................................................... 5682
2.4. GlucansynthesisInhibitors ...................................................................................... 5682
2.4.1. Echinocandins.......................................................................................... 5682
2.4.2. Caspofungin ........................................................................................... 5683
2.4.3. Micafungin ............................................................................................ 5683
2.4.4. Anidulafungin.......................................................................................... 5683
2.5. Chitinsynthesisinhibitors ....................................................................................... 5683
2.5.1. Nikkomycin............................................................................................ 5683
Correspondingauthor.
⇑
E-mailaddress:[email protected](M.KKathiravan).
0968-0896/$-seefrontmatter!2012ElsevierLtd.Allrightsreserved.
http://dx.doi.org/10.1016/j.bmc.2012.04.045
M.KKathiravanetal./Bioorg.Med.Chem.20(2012)5678–5698 5679
2.5.2. Polyoxins.............................................................................................. 5683
2.6. Nucleicacidsynthesisinhibitors.................................................................................. 5683
2.6.1. Flucytosine ............................................................................................ 5683
2.7. Proteinsynthesisinhibitors:sordarins ............................................................................. 5684
2.8. Microtubulessynthesisinhibitors ................................................................................. 5684
2.8.1. Griseofulvin............................................................................................ 5684
3. Recentadvancesinantifungalagents.................................................................................... 5684
3.1. Imidazole..................................................................................................... 5684
3.2. Benzimidazole................................................................................................. 5685
3.3. Quinazoline................................................................................................... 5686
3.4. Quinoline..................................................................................................... 5686
3.5. Quinazolinone................................................................................................. 5686
3.6. Isoquinoline................................................................................................... 5686
3.7. Analoguestoflucanazoleandtriazole.............................................................................. 5686
3.8. Benztriazole................................................................................................... 5690
3.9. Indole........................................................................................................ 5690
3.10. Napthalene................................................................................................... 5691
3.11. Napthoquinone............................................................................................... 5691
3.12. Thiazole..................................................................................................... 5691
3.13. Benzoxazole.................................................................................................. 5692
3.14. Pyrrole...................................................................................................... 5692
3.15. Pyrazole..................................................................................................... 5693
3.16. Pyrazoline ................................................................................................... 5693
3.17. Piperidine.................................................................................................... 5693
3.18. Morpholine .................................................................................................. 5693
3.19. Phenothiazine ................................................................................................ 5693
3.20. Thiophene ................................................................................................... 5693
3.21. Benzofuran................................................................................................... 5693
3.22. Benzopyrone ................................................................................................. 5693
3.23. Lactone...................................................................................................... 5693
3.24. Benzotriazine................................................................................................. 5694
3.25. Chromane ................................................................................................... 5694
3.26. Chalcone .................................................................................................... 5694
3.27. Oxadiazole................................................................................................... 5695
3.28. Pyrimidinone................................................................................................. 5695
3.29. Isoxazolidine................................................................................................. 5695
3.30. Carbazole.................................................................................................... 5695
3.31. Acetazolamide................................................................................................ 5695
3.32. Miscellaneous ................................................................................................ 5695
4. Conclusion ......................................................................................................... 5696
Referencesandnotes............................................................................................... 5696
1.Introduction There is considerable alarm amongst the medical profession
regarding fungal disease. Dermatophyte infections such as tinea
Fungal infections pose a continuous and serious threat to hu- pedisandcandidiasis,althoughrarelyfatal,arecommonandwide-
man health and life.1 These fungal infections in humans can be spreadthroughouttheworld.PathogenssuchasCandidaalbicans,
classified into (a) allergic reactions to fungal proteins, (b) toxic Cryptococcus neoformans, Pneumocystis carinii and Aspergillus
reactions to toxins present in certain fungi and (c) infections fumigatus are the causes of considerable morbidity and mortality
(mycoses).Healthyindividualsaresusceptibletoahostofsuperfi- inimmuno-compromisedpatients.8
cial, cutaneous, subcutaneous and in certain instances, systemic Aspergillus and Candida spp. account for the majority of docu-
infectionsthatcauseavarietyofconditionsrangingfromAthletes mented infections. Recent epidemiological trends indicate a shift
footandnailinfectionstoseverelife-threateningdisseminateddis- towards infections by Aspergillus spp., non-albicans Candida spp.
ease(e.g.,histoplasmosis).2Manyfungalinfectionsarecausedby and previouslyuncommonfungithat often havediminishedsus-
opportunistic pathogensthatmay be endogenous(Candidainfec- ceptibility to current antifungal agents.9–13 Clinically, candidiasis
tions)oracquiredfromtheenvironment(Cryptococcus,Aspergillus and aspergillosis account for between 80% and 90% of systemic
infections).1 fungalinfectionsinimmunocompromisedpatients.14
Theothertypeoffungalinfection,thatis,invasivefungalinfec- Although, the arsenal of antifungal drugs has expanded, cur-
tions and dermatomycoses produced by fungal organisms in the rently available antifungal drugs do not meet the increasing
individuals with increased vulnerability such as neonates, cancer requirementsofmanaginginfectioninthecomplexpatientpopu-
patients receiving chemotherapy, organ transplant patients, and lations. The development of new antifungal drugs has been con-
burnspatients,apartfromthosewithacquiredimmunodeficiency stantlyrequiredintheclinicaltherapy.15
syndrome (AIDS). Other risk factors include corticosteroid and
antibiotic treatments, diabetes, lesions of epidermis and dermis, 1.1.Candidaalbicans
malnutrition,neutropeniaandsurgery.3–6Inrecentyears,theinci-
denceandseverityoffungaldiseaseshasincreased,particularlyin ThemajorpathogenhasbeenC.albicans,normallyacommensal
patientswithimpairedimmunity.Thegrowingnumberofcasesof oftheoralcavityandgastrointestinaltractofhumans.Non-albicans
fungiinvolvedinsepsisisaconsistenttrend.7 Candida spp. (e.g., C. glabrata, C. tropkalis, C. krusei), however, are
5680 M.KKathiravanetal./Bioorg.Med.Chem.20(2012)5678–5698
Figure1. Targetsforantifungaltherapy.
alsofoundwithincreasingfrequency.16C.albicansandotherCan- Aspergillus is virtually ubiquitous. The microorganism acts as
didaspp.areregardedascommonconstituentsofthebodymicro- opportunistic pathogen in severely debilitated patients. Penetra-
biotainhealthyhumans.17Candidainhibitsthemucosalsurfacesof tion of the skin for placement of a catheter, the use of cytostatic
thehumanbody.18TherearesevenCandidaspp.ofmajormedical drugs that damage the mucosa, neutropenia and malabsorption
importance,themostimportantbeingC.albicans,theonemostfre- pavethewayforIFIs.18A.fumigatusisthemostcommonaetiolog-
quentlyisolated.Itisbelievedtobethemostvirulentinman.The icalagent,althoughotherspecies,suchasA.flavus,A.nigerandA.
other Candida spp. encountered in human infections is Candida terreus,areincreasinglyreported.29,30
tropicalis, Candida glabrata, Candida parapsilosis, Candida stellatoi- Non-albicans Candida, non-fumigatus Aspergillus and moulds
dea,Candidakrusei,andCandidakyfer.19 otherthanAspergillushavebecomeincreasinglyrecognisedcauses
Theincidenceofinfectionscausedbynon-albicansCandidaspp. ofinvasivediseases.ThemajorityofAspergillusspp.issusceptible
such as C. glabrata and C. parapsilosis is also more and more fre- to amphotericin B, extended-spectrum triazoles and the echino-
quently reported.20–24 C. albicans can cause chronic, superficial candins.Whereas,A.terreusisconsideredtobeparticularlyresis-
infections in otherwise healthy individuals; a prime example is tant to amphotericin B, it remains susceptible to extended-
vaginalcandidiasis.Although,C.albicansisrecognizedasthemost spectrum triazoles and the echinocandins.25,31 The epidemiology
commonpathogenamongtheCandidaspp.,inrecentyearsother of invasive aspergillosis indicates an increasing number of infec-
Candida spp., have been isolated with increasing frequency from tionsinimmunosuppressedpatients/individualsundergoingtrans-
clinicaldisease.20 plantation of bone marrow, hematopoietic stem cells, or organ
AmongthefivecommonCandidaspp.,C.albicans,C.parapsilosis transplantations, and those receiving intensive chemotherapy or
and C. tropicalis remain susceptible to polyenes, flucytosine, the otherimmunosuppressivetreatment32.
azoles and the echinocandins. C. glabrata is inherently either
dose-dependentlysusceptibleorresistanttofluconazole.C.krusei 2.Targetsforantifungaltherapy
isknowntoshowintrinsicresistancetofluconazole,anddecreased
susceptibilityofC.kruseitoamphotericinBhasalsobeenreported. Differenttargetsforantifungaltherapyisshownin(Fig.1)
Newtriazoles,suchasvoriconazoleandposaconazole,andtheech-
inocandins are active against these two species, although cross- 2.1.Fungalergosterolsynthesisinhibitors
resistance was noted within the azoles in some C. glabrata
strains.25 Ergosterolisthemajorcomponentofthefungalcellmembrane.
Itisasabioregulatorofmembranefluidity,asymmetryandinteg-
1.2.Aspergillusniger rity.Inhibition ofthe 14a-demethylasewillresult in adecreased
ergosterolsynthesisandaconcomitantaccumulationof14-meth-
Aspergillus niger Van Tieghem causes a disease called black ylatedsterols.Theypreventthe14-ademethylationoflanosterol
mould.26 It is a filamentous fungus growing aerobically on or- into ergosterol in the ergosterol synthetic pathway.33,34 Thereby
ganic matter.27 The Aspergilli are a large and diverse genus preventing the post-squalene synthesis segments such as the
( 180 species) of filamentous fungi including several well oxidosqualenecyclasemethyltransferase.35Ergosterolplaysahor-
!
known species with substantial commercial value (Aspergillus mone-likeroleinfungalcells,whichstimulatesgrowth,thenetef-
oryzae and A. niger) and medically significant molds; both as fectofazolesistheinhibitionthefungalgrowth.36–38
pathogens (Aspergillus parasiticus and Aspergillus fumigatus) and
toxin-producing contaminants of food and feed (Aspergillus 2.1.1.Azoles
flavus), as well as lesser-known but valuable species such as Theazoleantifungalagentsblockthesynthesisofergosterol,a
Aspergillus terreus.28 majorcomponentoffungalcytoplasmicmembranes.7,39
M.KKathiravanetal./Bioorg.Med.Chem.20(2012)5678–5698 5681
Cl
O O O O CH3
Cl N N O O N N N N CH3
N N Cl N
N
2
1 Cl CN
F
CH
NN NHO NFNN NN NHO F3N N N NHO CH3 NS
N F
F
F
F
3 4 6
O
N N O O
O N
N Cl N N N
N HO
O
Cl 5 CH3
N CH
CH 3
3
O N CH3
HC
3 O F
O
CH3 8
7 OH
OH
HC O OH
3
HO O OH OH OH OH O OH
CH
3 H
O
HC
3
HC O O
3
9
HO OH
NH
CH 2
3
HO O O CH
3
OH
CH
H C 3 OH HO
3 OH
O CONOHH2
O OH OH OH OH O OH
10
Figure2. Antifungalagents:Azoles,squaleneepoxidaseinhibitorsandergosteroldisruptors.
2.1.2.Ketoconazole blastomycosis, including chronic cavitary pulmonary disease and
Ketoconazole1(Fig.2)wasthefirstorallybioavailableimidaz- disseminated nonmeningeal histoplasmosis47,48 chronic pulmon-
ole.40andisafirstsignificantbroadspectrumantifungalazole.Itis aryaspergillosis,allergicsyndromesrelatedtoAspergillusspp,ony-
effective in patients with candidiasis, coccidioidomycosis, blasto- chomycosis,histoplasmosis,blastomycosisandsporotrichosis.49It
mycosis, histoplasmosis, paracoccidioidomycosis and cutaneous is not as good as fluconazole in acute cryptococcal infection and
dermatophyteinfections.41Ketoconazolerevolutionisedthetreat- as maintenance therapy for cryptococcal meningitis in AIDS pa-
ment of oral candidiasis, coccidioidomycosis, endemic mycoses, tients.39,46ItraconazoleislicensedintheUnitedStatesforsalvage
dermatophyte infections and veterinary fungal infections,42 but therapyofIA50andapprovedfortreatmentofallergicbronchopul-
has been now replaced.39 The most frequently reported adverse monaryaspergillosis50,51
sideeffectsaregastrointestinalinorigin,buttheseareusuallyre-
lieved with concomitant food administration,43 fatal toxic 2.1.4.Fluconazole
hepatitis.44 In1994,fluconazole3(Fig.2)wasapprovedforuseasasingle
oraldosetreatmentforvaginalcandidiasis.52Fluconazoleiseffec-
2.1.3.Itraconazole tivefortreatingoropharyngeal,oesophagealandvaginalcandidia-
Itraconazole2(Fig.2)wasthefirstorallybioavailableagentwith sis, as well as peritonitis, non-neutropenic patients with
anti-Aspergillusactivity39,45,46andusefulintreatmentofnonmen- candidaema, disseminated candidiasis(includingneutropenicpa-
ingeal, non-life threatening pulmonary and extrapulmonary tients),hepatospleniccandidiasis,funguriaandfocalurinarytract
5682 M.KKathiravanetal./Bioorg.Med.Chem.20(2012)5678–5698
infections. Fluconazole is also effective in pulmonary or dissemi- 2.2.3.Terbinafine
nated cryptococcosis, acute cryptococcal meningitis, for life-long Terbinafine8(Fig.2)isanallylaminethathasbeenavailablein
maintenance therapy, as primary prophylaxis for cryptococcal the United States since May 1996. Terbinafine has good in vitro
infections, in treating coccidioidal meningitis,39 oropharyngeal activity against Aspergillus spp., Fusarium spp. and other filamen-
candidiasis.53AfterinductiontherapywithAmphotericinBandflu- tous fungi but has variable activity against yeasts.39 Terbinafine
cytosine,fluconazoleisusedforsuppressionofcryptococcosis.54It hasbeenshowntobefungicidalagainstdermatophytes,Sporothrix
isextensivelyusedforthepreventionandtreatmentofsuperficial schenckii,dimorphicfungi,ScopulariopsisbrevicaulisandHerderson-
and invasive Candida infections.55,56 The bioavailability of fluco- ulaandAcremoniumspecies.36Amorolfinecanbeusedonlyfortop-
nazoleisveryhighcomparedwithotherazoles,likelytoitshigher icaltreatmentofsuperficialmycoses,andneitherofitstargetshas
watersolubilityandlowaffinityforplasmaproteins.39 attractedrecentresearchinterest.72
2.1.5.Voriconazole 2.3.Ergosteroldisruptors(polyenesantibiotics)
Voriconazole 4 (Fig. 2) is the first available low molecular
weight, water soluble second generation triazole and approved Ergosterol is the main component of the fungal cell. Polyenes
forfirst-linetreatmentofinvasiveaspergillosis,Oesophagealcandi- antibiotics form complex with ergosterol and disrupt the fungal
diasis.57–59 It is active against Aspergillus spp, Fusarium spp. and plasmamembranethatresultsinincreasedmembranepermeabil-
Candidaspp.(includingthefluconazoleresistantorlesssusceptible ity,theleakageofthecytoplasmiccontentsandultimatelydeathof
spp.ofC.glabrataandC.krusei).59Italsoshowsactivityagainstthe the fungal cell. Thus, the polyenes are fungicidal and have the
Fusarium and Scedosporium infections which are hard to treat.60 broadest spectrum of antifungal activity of any of the clinically
SideeffectsofVoriconazoletherapyincludeskinrashandtransam- availableagents.39,52,54
inaseelevation,61encephalopathyorhallucinations.62–64
2.3.1.AmphotericinB
AmphotericinB9(Fig.2)wasisolatedfromS.nodosumbindto
2.1.6.Posoconazole
sterolsincellmembranesandcausethemtoleakcellularconstit-
Posoconazole 5 (Fig. 2) was approved by the FDA in 2006 for
uents. Because they bind with up to 10 times more avidity to
prophylaxis against invasive Aspergillus and Candida infections.65
ergosterol, the sterol in fungal membranes, than to cholesterol
Posaconazole is a lipophilic second-generation antifungal tria-
thehumanmembranesteroltheyshowselectiveantifungalactiv-
zole with a similar molecular structure to that of itraconazole.66
ity.59AmphotericinBhavebroadspectrumofactivityagainstBlas-
It has in vitro activity against a variety of pathogenic fungi,
tomycesdermatitidis,Coccidioidesimmitis,Cryptococcusneoformans,
including Aspergillus, Candida spp., Cryptococcus spp., and
Histoplasma capsulatum, Paracoccidiodes brasiliensis, Sporotrichium
Histoplasma spp. It is good against infections caused by the
speciesandTorulopsisglabrata.Adversesideeffectsassociatedwith
zygomycetes than voriconazole. 67,68 The most frequent side
amphotericin B are infusional toxicity, nephrotoxicity and low
effects of posaconazole therapy are gastrointestinal (14%), with
bloodpotassium.39,75
transaminase elevation and hyperbilirubinemia occurring in
3%,69 gastrointestinal complaints (nausea, vomiting, abdominal
2.3.2.Nystatin
pain or diarrhoea) and headache,70,71 elevation of liver enzymes
Nystatin10(Fig.2)wasdiscoveredin1950fromthefermenta-
and skin rash.70
tionbrothofStreptomycesnoursei,andisstillusedasatopicalanti-
fungalagent.50Itisnonabsorbableafteroraladministrationbutis
2.1.7.Ravuconazole
effectivetopicallyinthetreatmentoforopharyngealcandidiasis.
Ravuconazole6(Fig.2)ishighlyactiveagainstawiderangeof
fungi, including Candida spp., even isolates that are resistant to
2.4.GlucansynthesisInhibitors
fluconazole.57,71,72 The efficacy of ravuconazole in O. candidiasis
in human immunodeficiency virus (HIV) patients has been com-
Glucans are the major components that strengthen the cell
paredwiththatofFluconazole.57
wall.33,58 The glucan polysaccharide consists of D-Glucose mono-
mers attached to each other by b-(1,3)-glucan or b-(1,6)-glucan
2.2.Squaleneepoxidaseinhibitors:morpholinesand linkages. This component is essential for the cell wall assuring
allylamines importantphysicalproperties.33,73Theblockageofglucansynthase
causesadecreasedincorporationofglucosetotheglucanpolymer,
Squaleneepoxidase,anenzymewhichtogetherwithsqualene hencetheinhibitorscausethelysisofthesusceptiblefungalcells.
cyclase,convertssqualenetolanosterol,whichwheninhibitedpre- Thefungalcellwallhasnocounterpartinthemammaliancells.75
ventstheconversionoflanosteroltoergosterol.39,45 b-(1,3)-Glucan synthase is inhibited noncompetitively by papul-
acandins and echinocandins.72 Depending on the concentration,
2.2.1.Morpholines it can either induce or inhibit the macrophage release of tumor
Morpholines 7 (Fig. 2) was discovered in the 1970s, are com- necrosis factor-a.33,76,77 The mode of action of echinocandins is
pletely synthetic compounds. Most of them have been used suc- based on the inhibition of cell wall b-glucan synthesis, a specific
cessfully in agricultural applications and amongst them only noncompetitiveinhibition(b-glucansynthase).33,78–82
amorolfineisusedinthetopicaltreatmentofnailinfections.1,59
2.4.1.Echinocandins
2.2.2.Amorolfine Echinocandins 11 (Fig. 3) are amphiphilic lipopeptides, prod-
Itpossessesbothfungistaticandfungicidalactivityinvitro.Two uctsofcyclopentamine,whichisformedduringthefermentation
sitesofantifungalactionhavebeenindicatedtheD7–D8isomerase of some fungi such as Zalerion arboricola or Aspergillus nidulans
andtheD14reductase,twofurtherenzymesinergosterolbiosyn- var. echinulatus.63,83 The mechanism of action include inhibition
thesis.Inhibitionbyamorolfineleadstohyperfluidityofthemem- of(1,3)-b-D-glucansynthase,whichproducesanimportantcompo-
brane, which causes changes in membrane permeability and, in nentofthecellwallofmanypathogenicfungisuchasCandidaspp.
addition, induces abnormal chitin deposition leading to growth andAspergillusspp.Inhibitionleadstodisruptionofthestructure
abnormalities.47 ofthegrowingcellwall,resultinginosmoticinstabilityanddeath
M.KKathiravanetal./Bioorg.Med.Chem.20(2012)5678–5698 5683
R clinicaltrialswerehypotension,vomiting,constipation,nausea,fe-
3 OHR4 OH ver,hypokalaemiaandelevatedhepaticenzymes.57,90
O
NH
N R5 2.5.Chitinsynthesisinhibitors
O NH
R
2
NH HN O Chitinisanimportantpolysaccharideinthefungalcellwallthat
O OH
O isimportantindeterminingcellshape,althoughpercentageofchi-
HO
NH N CH3 tin in the cell-wall is only about 1%.33,91–93 Chitin is practically
insoluble polymer consisting of b-(1,4)-linked N-acetylglucosa-
R1 OHO mine units. It is well separated from the glucan in the cell-wall,
OH
butitiscovalentlylinkedtoitinordertostrengthenthecell-wall.
HO
11 Chitin is essential for the fungi, it is absent in human organism.
Therefore chitin synthase signifies an attractive target of the re-
Figure3. Echinocandins. searchforantifungalagents.33
of susceptible yeast cells.84 The target of echinocandins does not 2.5.1.Nikkomycin
existinmammaliancells,sotheirtoxicityisminimal.57Thegen- Nikkomycin 15 (Fig. 4) is active toward the highly chitinous
eralstructureforechinocandinseriesisshowninTable1.85,86 dimorphicfungalpathogens,forexample,C.immitis,B.dermatitidis
andH.capsulatum.91IthaslittletonoactivityagainstC.albicans,C.
2.4.2.Caspofungin tropicalis.Itcanbeusedincombinationwithcaspofunginshowing
Caspofungin 12 (Table 1) was approved by FDA for the treat- fungicidalactivityagainstA.fumigates.33Itcanbeusedincombina-
ment of patients with IA.57Caspofungin 12 has potent in vitro tionwithcaspofunginshowingfungicidalactivityagainstA.fumi-
inhibitory activity against Aspergillus spp. and moderate activity gates.92,94
against some other moulds such as H. capsulatum, C. immitis and
B. dermatitidis. It is also active against P. carinii and moderately 2.5.2.Polyoxins
againstdematiaceousfungi.ButithasnoactivityagainstC.neofor- Polyoxins 16 (Fig. 4) show marked selective antifungal effect
mans, Trichosporon spp., Fusarium spp., S. schenckii, zygomycetes against the phytopathogenic fungi, however they are inactive to-
and hyalohyphomycetes.82,83 Caspofungin has few significant wardbacteria,plantsandanimals.33
interactionsasitisneitherasubstratenoraninhibitorofthecyto-
chromeP-450system.57Caspofunginhasfewsideeffects,consist- 2.6.Nucleicacidsynthesisinhibitors
ingmainlyofheadache,fever,nausea,rash,phlebitisatthesiteof
infusionandreversibleelevationofhepaticenzymelevels.57 Flucytosine interfares with pyrimidine metabolism, RNA/DNA
andproteinsynthesis.84Flucytosineisconvertedto5-fluorouracil
2.4.3.Micafungin by a cytosine deaminase, and later, by UMP pyrophosphorylase
Micafungin13 (Table1) was approved for the treatmentof O. into 5-fluorouridylic acid, which is further phosphorylated and
candidiasisaswellasprophylaxisinpatientsundergoingstemcell incorporated into RNA, resulting in disruption of protein synthe-
transplantation.57 Micafungin is found to be effective against O. sis. 5-Fluorouracil is converted to 5-fluorodeoxyuridine mono-
candidiasisandshowntobesuperiorthanfluconazolewhengiven phosphate, a potent inhibitor of thymidylate synthase.84,88 This
as prophylaxis in stem cell transplantation. Micafungin is shown enzyme is involved in DNA synthesis and the nuclear division
lessdruginteractionthancapsofungin.80,87 process.89
2.4.4.Anidulafungin 2.6.1.Flucytosine
Anidulafungin 14(Table 1) was approved for use in thetreat- Flucytosine17(Fig.4)wasfirstdevelopedasanticanceragent
mentofO.candidiasis,candidaemia,peritonitisandintraabdominal butlateronitwasscreenedforantifungalagentandtodayitisused
abscesses due to Candida spp.57 It is unique in echinocardins be- inadjunctivetherapywithAmphotericinBlikeCryptococcusneo-
causeitslowlydegradesinhumans,undergoingaprocessofbio- formans.95 It works as an antifungal agent through conversion to
transformation rather than being metabolized.57,88 It is highly 5-fluorouracil within target cells. Fluorouracil becomes incorpo-
activeinvitroagainstawiderangeofCandidaspp.,includingspe- ratedintoRNA,causingprematurechaintermination,anditinhib-
ciesthatareresistanttoazoles(C.krusei),amphotericinB(C.lusi- its DNA synthesis through effects on thymidylate synthase. Most
taniae)orotherechinocandins(C.parapsilosis)74,89andalsoagainst filamentousfungilacktheseenzymesandhenceusefulspectrum
Aspergillusspp.53Themostcommonadverseeffectsreportedfrom offlucytosineisrestrictedtopathogenicyeasts(Candidaspp.and
Table1
Showingsubstitutionforechinocandin(11)
Nameofcompound R1 R2 R3 R4 R5
O
Capsofungin(12) H NH2(CH2)2CHOH H NH(CH2)2NH2
O
Micafungin(13) HOSO3 NH2(CO)CH2CHOH CH3 OH N O
O
Anidulafungin(14) H CH3CHOH CH3 OH O
O
5684 M.KKathiravanetal./Bioorg.Med.Chem.20(2012)5678–5698
HO R 2.8.Microtubulessynthesisinhibitors
CH O COOH 1
3 O
N OH NH2 NHHO OOHNO NH OR2OOC O N ONH emuekMrasr.i9yc6rootTitcuhbecuyellelfsso.raTmrheeadayghneiagnmhtsliyclipokoerlgyagmnriieszeresodfoufclveailnl-u,alavnridnbsbkl-aetsultebitnuonliinntinedriamacl-tl
HN OH with b-tubulin, a protein highly conserved in eukaryotes. There
15 O R3 O OH may be differences between mammalian and fungal tubulins, for
HN example,colchicinebindspreferentiallytomammaliantubulin.97
2
NH2 F HO OH O O OH NH2 16 2.8.1.Griseofulvin
N
Griseofulvin19(Fig.4)wastheearliestchemicalthatcouldbe
O N O O OCH3O CH3 claimedtohaveaselectiveinhibitoryactivityagainstfungi.90Gris-
H eofulvin interferes with intracellular microtubule production,
17 O whichinhibitsfungalmitosis.98,99Theselectivetoxicityofgriseo-
HCO O fulvin for fungi is only moderate (liver toxicity is recognised as
O18OH 3 Cl 19 OCH3 amnaionclycatsoiotnhael dhearzmaradt)opahnydteitfsunsgpiecctaruusmesooff aricntgiownorismraenstdricattehd-
lete’s foot.45,95,99 The classification of antifungal agents are listed
Figure 4. Anti fungal agents: Chitin synthesis inhibitors, nucleic acid synthesis
inTable2
inhibitors,proteinsynthesisinhibitors,&microtubulessynthesisinhibitors.
3.Recentadvancesinantifungalagents
Candida neoformans).95 Flucytosine is used as adjunctive, rather
than primary therapy in clinic because of development of 3.1.Imidazole
registence.73
A series of compounds belonging to nitroimidazole were syn-
2.7.Proteinsynthesisinhibitors:sordarins thesized,evaluatedforantibacterialandantifungalactivity.There-
sults indicate that alkyl substitution at R in 20 showed good
Sordarins,18(Fig.4)hasbeenidentifiedasselectiveinhibitors antibacterialactivitywhereaspiperazinoalkaneshowedantifungal
of fungal protein synthesis. Sordarin was isolated from Sordaria activitylikemiconazole.Thecompoundwithtriazoleattachedto
araneosa in 1971.47 The sordarins group are protein synthesis sulphur has also shown antibacterial activity. The best activity
inhibitorsthatworkbyblockingthefunctionoffungaltranslation. among the series is the compound bearing phenyl piperidine at
Sordarins are absent in mammalian cells or electron transport R position in 20 (Fig. 5) against Trichophyton tonsurans with
chain.38 minimuminhibitoryconcentration(MIC3lg/mL),exertingabout
Table2
Classificationofantifungalagents.
Class Agent Mechanism Indication Toxicity
ofaction
First Fluconazole A ActiveagainstmostCandidaspp. Gastrointestinalintolerance
generation
triazole
Itraconazole A Anti-Aspergillusactivity Fluidretention,leftventriculardysfunction,
gastrointestinalintolerance
Ketoconazole A Candidiasis,coccidioidomycosis,blastomycosis,histoplasmosis, Gastrointestinal,hepatitis
paracoccidioidomycosisandcutaneousdermatophyteinfections
Second Voriconazole A Invasiveaspergillosis Elevationoftransaminasesandvisual
generation disturbances,rashandgastrointestinal
triazole symptoms
Posoconazole A ProphylxisofinvasiveaspergillosisandCandidainfection Nausea,vomiting,headache,abdominalpain
anddiarrhea
Ravuconazole A Activeagainstawiderangeoffungi,includingCandidaspp.,C. Gastrointestinal
neoformansandotheryeastspecies,
Echinocardin Caspofungin B PotentactivityagainstAspergillusspp.,Oesophagealcandidiasis Headache,fever,nausea,rash,phlebitis
Micafungin B TreatmentofOesophagealcandidiasis Nausea,vomiting,headache,diarrohea,
phlebitisandleukopenia
Anidulafungin B ActiveagainstCandidaspp.,Oesophagealcandidiasis Hypotension,vomiting,constipation,nausea,
fever,diarrhoeahypokalemiaandelevated
hepaticenzymes
Antibiotics Nystatin C Superficial(mucosal)candidainfectionsoftheoropharynx, Nephrotoxicity
oesophagusandintestinaltract
Amphotericin C Broad-spectrumofantifungalactivity Nephrotoxicity,Infusionaltoxicity,lowblood
B potassium
Griseofulvin D Forthetreatmentofcutaneousmycoses Livertoxicity
Nucleoside Flucytosine E ActiveagainstCandidaandAspergillusspp. Bonemarrowtoxicity
analogues
Allylamine Terbinafine F Usedforfungalnailinfections Mildrash,nausea,lossoftaste
A=interactwithcytochromep-450;inhibitC-14demethylationoflanosterol,therebycausingergosteroldepletionandaccumulationofaberrantsterolsinthemembrane,
B=theD7–D8isomeraseandtheD14reductaseinhibition,C=glucansynthaseinhibitors,D=Interactwithergosterol,therebydisruptingthecytoplasmicmembrane,
F=inhibitsthymidylatesynthaseandtherebyDNAsynthesis,G=inhibitsqualeneepoxidase.
M.KKathiravanetal./Bioorg.Med.Chem.20(2012)5678–5698 5685
X X
O2N HO N
CHCH2 R R
N CH S C N N
N 2 S N O N
N
CH
3
R'
20 21 R2 R
1
X X R1 N 22 R
R
N R2 N 5 O2N R2
N O N N R3 R4 N N
N
N
X X O R1
X X
24
23 25
H
PhHCHC Ph CH2CH2Ph H N R
2 2 O N N
N N A N
HN
N N 2 N
N
Ph
H3CH2C O R NH
27 28
26
NH
O Ar O O Ar 2
O O Ar
N CN
N
N
N S N S Ar' N S
29 30
31
O Ar NH R R
2 4 5
N N R3
CN R
N S OH 1 R N
2
32 33 R1
34
Figure5. Antifungalagentswithvariousnulceouslikeimidazole,benzimidazole,quinazoline&quinoline.
onehalftheactivityofonidazole,howevernonewereaseffective strainsofCandidaspp.In23(Fig.5),monochloroderivativeswere
asmiconazole(MIC0.2lg/mL)orornidazole(MIC0.8lg/mL).100 more potent than N-unsubstituted compound. Introduction of a
Derivativesof1H-imidazol-1-amineweresynthesizedandeval- methyl or a pyrrolyl groups on the phenyl rings or replacement
uatedinvitroagainstseveralpathogenicfungiandcomparedwith of the phenyl with a naphthalene ring leads to less active com-
Miconazole. In 21 (Fig. 5) 2-Substituted phenyl compounds pounds.Theintroductionofone,two,orthreechlorineatomson
showedbetterresultsthan4-substitutedphenyl,especiallyagainst compounds lowers potency on R , R R . The most active com-
3 4 5
Candida neoformans. Inhibition of dermatophytes was less influ- pound are those bearing substitution at X=C H , CH =CH ,
3 7 2 2
enced by the aryl portion. The potent compound has R=R0=Cl, CH2CH=CH2,CH2CH=C(CH3)2,Ph,CH3,C2H5,HandR1=Cl,H,1-
withMIC0.8lg/mLandmiconazole0.4lg/mL,againstTrichophy- pyrrolylR =R =H,ClandR =H,Cl,CH andR =H,Cl.Thecom-
2 3 4 3 5
ton rubrum. Test pathogensincludedrepresentatives ofyeasts (C. pound where R =Cl, R =R =R =R =H, X=C H found to be
1 2 3 4 4 3 7
albicans,C.parapsilosis, Cryptococcusneoformans)dermathophytes mostpotentamongsttheserieswithMIC0.016lg/mL.103
(T. verrucosum, T. rubrum, Microsporum gypseum) and molds (A. Nitroimidazole derivatives have been synthesized and evalu-
fumigatus).101 ated against sclerophomapityophila. High effectiveness was ob-
Theseriesofinvertedoximeethersofoxiconazoleweresynthe- served with the introduction of nitro group at 4-position on the
sized22,23(Fig.5)andevaluatedagainstC.albicans,C.glabrata,C. imidazole ring in 25 (Fig. 5) bearing morpholine or piperidine
parapsilosis,A.fumigates,A.flavus,Trichophytonmentagrophytes,T. and by the presence with substitution R =H, R =morpholine,
1 2
rubrum.In22substitutionatX=Cl,FandR=Ethoxy,morpholine, piperidine ansX=Hshowsantifungalactivityofa chlorineatom
ClandR =Cl,F,HandR =H,Me,Et,Pr.showedbetterresults.In at4-positiononthephenylring.Thecompounds.104
1 2
fact the most potent against all of the strains tested, both yeast
fungi,suchasC.albicansandfilamentousfungianddermatophytes, 3.2.Benzimidazole
suchasAspergillusandTrichophytonwithMIC0.25–128lg/mL.In
23thesubstitutionatX=Cl,Fshowsantifungalactivity.102 Benzimidazole derivatives containing electron-rich olefines
TheN-substituted1-[(aryl)-(4-aryl-1H-pyrrol-3-yl)methyl]-1H- were synthesised. All compounds were screened in vitro against
imidazole derivatives were synthesized and tested against 12 the C. albicans and C. tropicalis. Most potent compound 28 and
5686 M.KKathiravanetal./Bioorg.Med.Chem.20(2012)5678–5698
29 (Fig. 5) with following structures and MIC 50lg/mL against O
C. albicans and C. tropicalis. The antifungal activity of this series F COOH
were related to spiro structure and hydantoin moiety. The struc-
ture29withA=seleniummoiety,R=CH3,C2H5alsoshowedgood N N
antifungalactivity.105 N
R
A series of 18 molecules belonging to 20-arylsubstituted-
35
1H,10H-[2,50]-bisbenzimidazolyl-5-carboxamidines were synthe-
sized and tested against C. albicans and C. krusei. Introduction of Figure 6. 1-Ethyl-6-fluoro-1,4-dihydro-4-oxo-7(1-piperazinyl) quinoline-3-car-
1-napthyl(R)showedMIC0.78lg/mLin28(Fig.5),greatoractiv- boxylicacid(norfloxacin)derivatives.
ity than fluconazole 0.74lg/mL and introduction of 2 napthyl
leads to eightfold reduction in activity with MIC 6.25lg/mL
againstC.albicans.106 Table3
Differentsubstitution at1-ethyl-6-fluoro-1,4-dihydro-4-oxo-7(1-piperazinyl)quino-
line-3-carboxylicacid(norfloxacin)derivatives
3.3.Quinazoline
Compound R(Substitutionat35)
Quinazolineshavebroadspectrumofbiologicalactivities.Three
O O
compoundsreportedinaseriesof15havegoodantifungalactivity
against Aspergillus ochraceus, C. albicans. The substitution bearing 36 O
Ar=p-FC6H4 in 29 (Fig. 5) and Ar=p-FC6H4, Ar0=p-ClC6H4 in 32
(Fig.5),showedmarkedantifungalactivitybutlessthanreference Cl O
drugTiconazole(trosyd).107
37
Fused quinazolin-5-one compounds were synthesized and
evaluatedforantifungalactivity.Thecompoundscontainingboth Cl
the quinazoline and pyrimidinothiazole moieties were found to
be the most active against A. ochraceus and A. flavus when com-
pared to trosyd with MIC 40lg/mL. The most active compounds C. albicans, A. fumigates, C. krusei. In 38 (Fig. 7) substitution with
amongst the series were 31 and 32 (Fig. 5) with Ar=aromatic R=3OCH3,4-ClandY=OTfdemonstratedsignificantinvivoeffi-
ring.108 cacy against C. albicans and C. neoformans comparable to that of
amphotericin B. The opening of the benzo[b]thiophene ring and
3.4.Quinoline replacing the N-methyl group with N-5-phenylpentyl or 5-cyclo-
hexylpentyl groups in 39 (Fig. 7) to form substituted 3-(phenyl-
A series ofquinoline derivativeswereprepared and testedfor thio)quinolinium compounds produced as high as 50-fold
in vitro antifungal activity on eight pathogenic fungi. The results increasesinpotencywithoutincreasingcytotoxicity.112
indicatethatsubstitutionintheC positionofthephenylringby
4
polargroup(phenolicornitromoiety)seemstobeveryimportant 3.5.Quinazolinone
for antifungal effect, as well as the presence and position of the
nitrogen atom in the connecting linker between the quinoline Derivativesof4(3H)-quinazolinoneweresynthesizedandeval-
andphenylring.Thesubstitutionwith2and3OHgroupatR in uatedforantifungalactivityagainstA.niger,C.albicansandFusar-
1
33(Fig.5)showedinvitroantifungalactivitycomparablethanthat iumoxysporum.ThepresenceoftheOCH3groupin40(Fig.7)atthe
ofthestandardfluconazole.109 phenylringdoesnotimpartanyactivity,butthepresenceofanal-
A new series of quinoline derivatives possessing an aromatic kylgroupCH3atthephenylringleadstobetteroutcomesthanfor
substituent(carbocyclicorheterocyclic)atC2positionweresyn- compoundswithanunsubstitutedphenylring.Thepresenceand
thesizedandscreenedforantifungalpropertiesagainstapanelof positionofthechlorineatomplaysacrucialrole,theorderofactiv-
standardizedfungiincludingyeasts,hyalohyphomycetesandder- ity being 4-Cl>3-Cl>2-Cl. The MIC range showed the best MICs
matophytes.Themostactivequinolinemoleculeswerethentested 0.016–0.125lg/mL,againstC.albicans,C.neoformans,A.fumigates
against a panel of clinical isolates. Results showed that the most withFluconazole0.5–4lg/mL.113
active compounds were 2-hetaryl quinolines particularly those
containing a c-pyridyl ring, a-Furyl (a-thienyl) derivatives were 3.6.Isoquinoline
devoid of antifungal properties. The different substituents were
tried in 34 (Fig. 5) like R =H, CH , OCH , i-Pr. and R =H, C H , A series of novel pyrazino[2,1-a]isoquinolin compounds were
1 3 3 2 2 5
CH andR =H,C H ,CH ,F,Cl,NO ,OHandR =H,CH .Theactiv- designed,synthesizedandevaluatedforantifungalactivityagainst
3 3 2 5 3 2 5 3
itycouldberelatedtotheC-4and/orC-8substitutiononthequin- C.albicans,Cryptococcusneoformans,T.rubrum,M.gypseum,A.fumi-
olineringandwouldberelatedneithertothelipophilicitynorto gates. The substitution with R1=H, R2=F, R3=(CH2)8CH3 in 41
thebasicityofcompounds.110 (Fig. 7) found to be most potent with MIC (4–16lg/mL) against
Aseriesof28moleculesbelongingto1-ethyl-6-fluoro-1,4-dihy- Cryptococcusneoformans,T.rubrum,M.gypseum,A.fumigateswith
dro-4-oxo-7(1-piperazinyl)quinoline-3-carboxylic acid (norfloxa- fluconazole (2–64lg/mL). Methoxy and hydroxyl substitution at
cin) derivatives (Fig. 6) were synthesized and tested for R1andR2showsgoodantifungalactivity.114
fungicidal action against Xanthomonas oryzae, Xanthomonas axo-
nopodis, Erwinia aroideae, Ralstonia solanacearum a plant patho- 3.7.Analoguestoflucanazoleandtriazole
genic fungi. The inhibition of growth by Compound 36 and 37
(Table.3)R.solanireached83%and94%,respectively,ataconcen- Novelfluconazole/bileacidconjugatesweredesignedandeval-
trationof200mg/Lwhichindicatedthattheiractivitieswererela- uatedforantifungalactivityagainstC.albicans,S.schenckii,C.par-
tivelyclosetocarbendazim(itsinhibitionofgrowthwas100%),a apsilosis. The substitution attempted were benztriazole,
commercialfungicide.111 benzimidazole, triazole, tetrazole in place of fluconazole in 42
Benzothieno[3,2-b]quinoliniumand3-(phenylthio)quinolinium (Fig.7)butdidnotshowanysignificantantifungalactivity.Substi-
compoundsweresynthesizedandevaluatedagainstC.neoformans, tutionwithR=H,OHshowsgoodantifungalactivityintherange
M.KKathiravanetal./Bioorg.Med.Chem.20(2012)5678–5698 5687
HC R R
3 N R1 I O S
R Y N N
R N N
S S
N CH
3
38 39 40
R
1
N F F
R N O N
2 N
N
H R N OH
41 R3 42 N N CF3
OH
N OH R N N R OHCH3 O n
N N N X N Z O
N F N
N F
X
F
43 CF 44 F 45
3 R
R 2
1
CH(CH)nCH
2 2 3
N N
N N
n N N N N CH
CHO H2C(CH2)n3
N 46 N 48 49
47
N
N OH R3 OH OH
N N N N RN N N O
X R N N F N F O R
R
1
X F F 52
50 51
Figure7. Antifungalagentswithvariousnulceouslinkquinolinium,quinazolinone,isoquinoline&antifungalanaloguesofflucanazoleandtriazole.
2.18–25lg/mL.Itisthoughtthatbileacidpartactsasadrugcar- bonds,showedexcellentin vitroactivityagainstCandida, Crypto-
rierandfluconazolepartactsasaninhibitorof14a-demethylase coccus,andAspergillusspp.Thesubstitutionofn=2givesmostpo-
enzymesinfungalcell.115 tent compound in the series with the MIC 0.016–0.125lg/mL,
Twenty three derivatives belonging to 1-(1H-1,2,4-triazole-1- against C. albicans, Cryptococcus neoformans, A. fumigates with
yl)-2-(2,4-difluorophenyl)-3-(N-cycloproyl-N-substituted-amino)- fluconazole0.5–4lg/mL.118
2-propanols were designed, synthesized and evaluated for anti- A series of 1,2,4-triazole and benzotriazole derivatives were
fungalactivity.Thetitlecompoundshadhigherantifungalactivity synthesizedandevaluated.Theazolecompoundsplusfluconazole
andbroaderantifungalspectrumthanfluconazolewithMICvalues werecharacterizedbyadockingmodeintheactivesiteofthecyto-
lessthan0.125lg/mL.Thesubstitutionin43(Fig.7)withR=CH chromeP45014a-steroldemethylase.SARstudyshowedthatthe
3,
4-C H CN showed potent activity 0.125-2lg/mL against C. albi- antifungalactivityisdependentontheheterocyclicmoietyaswell
6 5
cans,C.parapsilosis,C.neoformans,C.tropicalis,T.rubrum,A.fumig- asonthenatureofthesubstituents.Smallsizedcompoundsmay
atus,Microsporumcanis,Fonsecaeacompacta.116 beattributedtothebetterpenetrationintofungicell.Thebenzo-
Aseriesoffluconazoleanaloguesweresynthesizedandevalu- triazoles compounds had low antifungal activity and may be be-
atedinvitroagainsttwoclinicallyimportantfungi,C.albicansand cause of the presence of methoxy group on the triazoles and
A. fumigates. Heterocycles were introduced in place of R in 44 benzotriazolesmoiety.119
(Fig.7)suchasindole,azaindole,benzimidazole,benztriazole.The The design and synthesis of 1-[((hetero)aryl- or piperidinylm-
MIC valuesforazaindolederivativesindicatethatthemostactive ethyl)amino]-2-phenyl-3-(1H-1,2,4-triazol-1-yl)propan-2-ols,
80
compoundswerethe2,4-dichlorophenylwithazaindoleinplaceof were reported showing various degrees of antifungal activity
R.ThisparticularcompoundshowedremarkableactivitiesagainstC. against C. albicans and A. fumigatus. The 1-[(1H-indol-5-ylmethy-
albicans in particularly (IC =0.0007 and 0.0031lg/mL) which l)amino]derivativesexhibitedpotentMIC65ng/mLagainstC.albi-
80
weremuchmorepotentthanfluconazole(IC =0.020lg/mL).117 cans.Thebestresultwasobtainedwithfluorinatedcompound50
80
Anewseriesoftriazolecompoundspossessingasulfuratomin (Fig. 7) bearing a N-Boc protective group on the indole moiety,
placeofZwereefficientlysynthesizedandtheirinvitroantifungal introduction of a N-methyl group in the linker would not play a
activities were investigated against C. albicans, C. parapsilosis, C. majorroleonthetwotestedstrains.CompoundwithX=F,R=H,
glabrata,C.krusei,C.tropicalis,Cryptococcusneoformans,A.fumiga- R =Bocexhibitedmoderateantifungalactivitiesagainstallfungi
1
tus,A.flavus.Amongcompoundsin45(Fig.7)n=0,1,2,3andin46 testedwithMICvaluesrangingfrom3.8to33.0ng/mL,lowerthan
(Fig. 7) n=2, which has a side chain with two olefinic double thoseoffluconazole(190ng/mL).120