TurkJMedSci 31(2001)493-497 ©TÜB‹TAK ÖzlemTEM‹ZARPACI QSARsofSome5-or6-Methyl-2-Substituted Benzoxazoles/Benzimidazolesagainst Candidaalbicans Received:November07,2000 Abstract: QSARanalysisofsome5-or6- usingtheBILINstatisticalsoftware.The methyl-2-substitutedbenzoxazoles/ resultingQSARrevealedthatsubstitutionat benzimidazoleswasstudiedfortheantifungal positionYwiththeCH2 groupwassignificant activityagainst C.albicans usingHansch fortheimprovedantifungalactivity. analysis.Predictionfortheleadoptimization Moreover,hydrophobicpropertiesofthe inthisQSARanalysiswasdescribedbythe substituentsatpositionR 2 areindicativefor descriptionofvarioushydrophobic,electronic, theantifungalactivityagainstC.albicans. stericandstructuralparametersrelatedto KeyWords: Benzoxazole,Benzimidazole, DepartmentofPharmaceuticalChemistry, positionsR 1,R 2,R 5,R 6,X,Y.Thecross- Antifungalactivity,QSAR,Hanschanalysis FacultyofPharmacy,AnkaraUniversity, validationmethodwasalsoappliedtothedata Tando¤an06100,Ankara-TURKEY setinordertoprovethepredictivepowerby Introduction chemotherapy(5).Newdevelopmentshaveincludedthe Mycoticillnessesinhumansaredividedintothree modificationofexistingdrugmoleculestoeliminate groups:contagiousskinandhairinfections, toxicityandimproveactivity.Inshort,antifungaltherapy noncontagioussoilborneorairbornesystemicinfections hasadvancedrapidlyinthelastfewyearscomparedto andnoncontagiousfoodbornetoxemias.Theresponsible previousyearsandrecommendationsfortreatmentof organismsandmethodsofpreventionandtreatment fungalinfectionsarelikelytochangeinthenearfutureas differwitheachgroup.Theprevalenceofsystemicfungal ourunderstandingoffungalinfectionsimprovesandnew infectionshasincreasedsignificantlyduringthepast antifungaltherapiesarediscovered. decade.Thisincreaseisduetogreateruseofbroad- Biologicallyactivebenzoxazoleshavebeenknownfor spectrumantibiotics,immunosuppressiveagents,central alongtimeanditwasseenthatposition2isdecisivefor venouscatheters,intensivecarelowbirthweightinfants, thebiologicalactivity,whereasposition5determinesthe organtransplantationandtheacquiredimmunodeficiency intensityoftheiractivity(20-22). syndrome(AIDS)epidemic(1-13). Recently,wereportedthesynthesisandinvitro Significantantifungalchemotherapybeganin1903, antifungalactivitiesofdifferent5-or6-methyl-2- withthesuccessfuluseofpotassiumiodideforthe substitutedbenzoxazoles/benzimidazolesagainstthe treatmentofsporotrichosis.Exceptforthedevelopment fungusCandidaalbicans (23-25)(Figure1). offlucytosine,therewaslittleprogressuntiltheearly 1970sandthedevelopmentoftheazoledrugs.The R6 X currentera,whichischaracterizedlargelybythe YR2 modificationsofazoledrugs,beganwithmiconazoleand N ketoconazoleandbroughttheagentsfluconazoleand R5 R1 itraconazoleandravuconazole,whichcanbegivenorally andhaveincreasedpotency,decreasedtoxicityanda R1=H,Cl,F,NO2,CH3,OCH3 Y=—,CH2,CH2O,CH2S broaderspectrumofactivity(14-19). R2=H,Cl,Br,NH2,CH3,OCH3 X=O,NH R5=H,CH3 Inthepast10yearstherehasbeenamajorexpansion R6=H,CH3 inthedevelopmentofantifungaldrugs,buttherearestill Figure1. Antifungalactivesomebenzoxazoleandbenzimidazole weaknessesintherangeandscopeofcurrentantifungal derivativesagainstC.albicans. 493 QSARsofSome5-or6-Methyl-2-SubstitutedBenzoxazoles/Benzimidazolesagainst Candidaalbicans Anextrathermodynamicapproachintheanalysisof Fortheprocedureofdescriptorselectionrelatedto quantitativestructureactivityrelationships(QSAR)has theactivityamongthecandidatesetofvariables,forward beenmostwidelyandeffectivelyusedfortheoreticaldrug step-wisemultipleregressionofeliminationwasapplied. design.ThismethodhasalsobeencalledtheHansch Duringthedevelopmentofthebestfitmodelof approachanditassumesthatthepotencyofacertain correlationequation,theminimumFvalueforentering biologicalactivityexertedbyaseriesofcongeneric andremovingthevariablesinthestep-wisemultiple compoundscanbeexpressedintermsofafunctionof regressionwastakentobe8.0,whichisstatistically variousphysicochemical(electronic,stericand significantatthe1%levelofprobability(31). hydrophobic)effects(26-29).Thisassumptionis Inordertojudgethevalidityofthepredictivepower summarizedinanequationasfollows: oftheQSAR,thecross-validationmethodisalsoapplied f(biologicalactivity)=f(electronic)+f(steric)+f totheoriginaldatasetbyremovingagroupof (hydrophobic)+[f(structural)+f(therotical)] compoundsfromthedatainsuchawaythateach Ifthesefunctionscouldbeformulatedinanequation observation(compound)isdeletedonceandonceonly. showingcertaineffectsfavorablefortheactivity, Foreachreduceddataset,amodelisdevelopedandthe structuralmodificationsthatenhancesuchproperties responsevaluesofthedeletedobservationsarepredicted wouldbeexpectedtogeneratepotentactivecompounds. fromthismodel.Thecross-validationmethodwasalso appliedtothedatasetinordertojudgethevalidityof Multipleregressionanalysisinvolvingfindingthebest predictivepowerofthemodelandoverallPRESS fitofadependentvariable(microbiologicalactivity)toa (PredictiveResidualSumofSquare)valueswere linearcombinationofindependentvariables(descriptors) calculated(32). bytheleastsquaresmethodwasused(30).Thisis formallyexpressedasfollows: RegressionanalysisandcalculationswererunonaPC usingtheBILINstatisticalprogrampackage(33,34).In y=a0 +a1x1 +a2x2 +a3x3 +…….+a nxn theequations,thefiguresinparenthesesarethestandard whereyisrelatedtothemicrobiologicalactivityofa errorsoftheregressioncoefficients.Foragiven 2 compound,x 1,x 2,……x n arethedescriptorvalues equation,nisnumberofcompounds,r denotessquare relatedtotheactivityanda 0,a 1,a 2,…..a n arethe ofthemultiplecorrelationcoefficients,Fisthe regressioncoefficientsdeterminedbytheleastsquare significancetestandsrepresentstheresidualstandard analysis.Thisequationisdevelopedforeachcompoundin deviation. ourQSARstudy. Acongenericsetof5-or6-methyl-2- Inthispresentstudy,QSARanalysisofsome substitutedbenzoxazoles/benzimidazoles1-25were antifungalactive5-or6-methyl-2- consideredinthisstudy.Thecandidatesetofvariables substitutedbenzoxazoles/benzimidazoles,1-25givenin usedinthisanalysisincludeshydrophobic,electronic, Figure1,against C.albicans weredeterminedusing stericandstructuralparameters.Forthestructural Hanschanalysis. variablesI R6 wasdefinedas0forpossesingH,1for possesingCH 3 atpositionR 6;I R5 wasdefinedas0for possesingH,1forpossesingCH 3 atpositionR5;IyOwas Experimental definedas1forpossesingOatom;IyCH 2 wasdefinedas MultivariateHanschanalysisinQSARhasbeenmost 1forpossesingCH 2 group;IyCH2Owasdefinedas1for widelyandeffectivelyusedfortheoreticaldrugdesign possesingCH2Ogroup;IySwasdefinedas1forpossesing duetovariousphysicochemical(electronic,stericand CH2SgroupatpositionYandIxwasdefinedas1for hydrophobic)parametersandstructuralindicator possesingOatom,0forNHatomsatpositionX.The parametersbeingusedtogether.Theassumptioncanbe hydrogendonating/acceptingcapabilities(H DONOR/HACCEPT) formulatedasgivenintheequationbelow. ofthesubstituentsatR 1,R 2,R 5,R 6 weretheindicator Σ Σ variables. log1/C= aiIi + bjXj +c whereI isthestructuralindicatorparametersandX is Thescreenedphysicochemicalparametersinthis i j π thephysicochemicalvariables. QSARstudywere forthehydrophobiceffects,F(field 494 Ö.TEM‹ZARPACI effect),R(resonanceeffect)and σ astheelectronic ResultsandDiscussion influenceandMR,MW,Es,Es-V,Verloop’sSTERIMOL PredictionsfortheleadoptimizationinthisQSAR parameters(L,B 1,B 4)forthestericinteractionsofthe analysisofantifungalactive5-or6-methyl substituentsR 1,R 2,R 5 andR 6.Valuesforallcandidate benzoxazoles/benzimidazolesweredescribedbythe physicochemicalvariablesusedinthisQSARstudywere descriptionofvarioushydrophobic,electronic,stericand takenfromthetableofHanschetal.(14).Thevaluesof structuralparametersrelatedtopositionsR 1,R2,R5,R6, thedescriptorsrelatedtotheactivityamongthe X,Y.Oneleaveoutcross-validationmethodwasalso candidatetestsetofvariablesofthebestresultsinthe appliedtothedatasetinordertoprovethepredictive QSARanalysisareshownintheTable. powerbyusingtheBILINstatisticalsoftware.Compounds Table. Compoundsandtheparametersusedinthebestequation. R6 X YR2 N R5 R1 π Com. R1 R2 R5 R6 XY R2 IyCH2 MIC Obs. Cal. Residual No: µg/mL log1/C log1/C 1ClHCH3 HO 0 0 25 3.989 3.996 -0.007 2 OCH3 HCH3 HO 0 0 25 3.980 3.996 -0.015 3NO2 HCH3 HO 0 0 25 4.007 3.996 0.011 4ClClCH3 HO 0.71 0 25 4.046 4.024 0.023 5 CHH3 CH3 CH3 HO 0.56 0 25 3.977 4.018 -0.041 6 OCH3 OCH3 CH3 HO -0.02 0 25 4.032 3.995 0.037 7ClHHCH3 O 0 0 25 3.989 3.996 -0.007 8 OCH3 HHCH3 O 0 0 25 3.980 3.996 -0.015 9FHHCH3 O 0 0 25 3.958 3.996 -0.038 10 NO2 HHCH3 O 0 0 25 4.007 3.996 0.011 11 Cl Cl H CH3 O 0.71 0 25 4.046 4.024 0.023 12 CH3 CH3 HCH3 O 0.56 0 25 3.977 4.018 -0.041 13 OCH3 OCH3 HCH3 O -0.02 0 25 4.032 3.995 0.037 14HHCH3 HO CH2 0 1 12.5 4.251 4.298 -0.047 15 H Br CH3 HO CH2 0.86 1 12.5 4.383 4.332 0.051 16 H NH2 CH3 HO CH2 -1.23 1 12.5 4.280 4.250 0.030 17 H H H CH3 OCH2 0 1 12.5 4.251 4.298 -0.047 18HHCH3 HNHCH2 0 1 12.5 4.249 4.298 -0.049 19 H Cl CH3 HNHCH2 0.71 1 12.5 4.312 4.326 -0.014 20 H Br CH3 HNHCH2 0.86 1 12.5 4.382 4.332 0.049 21 H NH2 CH3 HNHCH2 -1.23 1 12.5 4.278 4.250 0.028 22HHCH3 HO CH2O 0 0 25 3.980 3.996 -0.015 23HHCH3 HO CH2S 0 0 25 4.009 3.996 0.013 24HHCH3 HNHCH2S 0 0 25 4.007 3.996 0.011 25 H Cl CH3 HNHCH2O 0.71 0 25 4.037 4.024 0.014 495 QSARsofSome5-or6-Methyl-2-SubstitutedBenzoxazoles/Benzimidazolesagainst Candidaalbicans andparametersusedinthebestequationandobserved, F:Fischervalue(measureofthestatistical calculatedandresidualvaluesaregivenintheTable.The significance) plotoftheobservedandcalculatedCvaluesofthe Q2:squaredcross-validationregressioncoefficient growthinhibitoryactivityofcompounds1-25against C.