The Antifungal Activity Of 2-(p-Substituted-Phenyl)Oxazolo (4,5-b)Pyridine derivatives Against

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FABAD Farın. Bil. Der.

12, 281 - 288, 1987

FABAD J. Pharm. Sci 12, 281 - 288, 1987

The Antifungal Activity Of 2-(p-Substituted-Phenyl)Oxazolo (4,5-b)Pyridine derivatives Against

Candida Albicans And The Quantitative Structure • Activity

Relationsh i ps

Esin ŞENER (*) İsmail YALÇIN (*) S•çkin ÖZDEN (*) Tuncel ÖZDEN ^(*) Ahmet AKIN (**) Sulhiye YILDIZ (**)

Summary : The antifungal activity of 2-(p-substltuted-phenyl)oxazolo (4,5-b)pyridine derivatives was determined using The DiJution Tech- nique. The compounds were found significantly active (MIC: 12.5-25 µg/ml).

The quantitative structure-activity relationships (QSAR) of the com·

pounds were studied using som·e hydrophobic ('lr, 7t2), electronic (Q, F, R) and steric (MR, MW, ·P_1-)physicochemical parameters. The cor- rel-ation eqtıations of these relationshipS which were de~igned according to the Hansch Analysis M.ethod w·ere given.

For the correlation of the antifungal activity against C. albicans with the molecular criteria in the series of 2-phenyloxazolo(4,5-b)pyridi-

(*) A.Ü. Eczacılık Fakültesi, Farmasötik Kimya Anabilim Dalı, Tan,

doğan - Ankara

(**) A.Ü. Eczacılık Fakültesi, Mikrobiyoloji Bilim Dalı, Tandoğan-An·

kara

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nes, the cornbinations of hydrophobic, electronic or steric parameters vvere found rnore significant as con1pared to hydrophobic, electronic or steric pararneters used separately. The best equation obtained frorn QSAR studies were stated.

2-(p-SÜBSTİTÜE-FENıİL)OKSAZOL0(4,5-b)l'İRİDİN TÜREVLERİNİN CANDİDA ALBİCANSA KARŞI ANTİFUNGAL ETKİLERİ VE

KANTİTATİF YAPI-ETKİ İLİŞKİLERİ

Öz~t: 2-(p-Siibstitüe-fenil)oxazolo(4,5-b)piridin tür:evlerinin C. <ilbi~

cansa karşı antifungal etkileri Tüpte Dilüsyon Yöntemi kullanılarak ça~

1ış1ln1ıştır. Hansch'ın Analiz yöntemine göre bulunan· korrelasyon denk- lemleri venilmiştir.

2-Feniloksazolo(4,5-b)piridin tütevleri ile C. albicansa karşı antifungal etki arasındaki ilişki incelenildiğinde, hidrofobik, elektronik ve ste- rik parametrelerin ayrı ayrı kullanılmaları yerine, kombine halde kul-

lanılmalarının anlan11ı olduğu bulunmuştur. QSAR çalışmalarından elde edilen ideal denklem belirtilmiştir.

Keywords : 2-(p-Substituted-pbenyl)oxazolo(4,5-b)pyridine, C. albicans, "' 71",

o,

F, R, MR, MW, Pr, Best equation.

INTRODUCTION

In our previous paper, the synthesis and stnıcture elucidations of 2-(p-substituted-phenyl)oxazolo

(4,5~b)pyridine derivatives were sta.

ted (1). In another report, we sta.

ted the quantitative stn1cture-acti.

vity relationships (QSAR) of these compounds in gram (-) bacteria.

In this research, we decided to study the antifungal activity of the compounds against C. albicans ·in order to design of more active compounds in these series. The an·

tifun2'al activity of these compo.

unds are thought as the function of the physicochemical paraıneters on lead optimization method.

We select sorne steric, electro.

nic and hydrophobic parameters which are shown in Table 2 for our quantitative structq.re activity re.

lationship studies. The multiplc regrcssion analys-is method is used vvhich rinvolves finding the best fit of a dependent variable (the mic, robiological acti.vity) to a linear combination of the independent va.

riables (descriptors) by the method of Ieast squares. This !İs formally expressed as follows;

where Xıı x_2, .... xn are ·the descriptor values (physicochemical substituent constants), y is related·

to the microbiological activity of

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oxazolopyridin derivatives, and a₀^, aıı . . an are the coefficients determined by a least squ.

ares analysis. This equation is de·

veloped fo reach oxazolopyridine derivative in our analysis.

MATERIAL AND METHOD Antifungal Activity

For antifungal activity Candida albicans RSKK 628 were chosen.

T·he .antifungal activity were tested as described earlier (3,4).

The activ.ity of the compounds against C. albicans w·ere tested ]n Swbouraud¹s broth- (Neopeptone:

10 g, Dextrose: 40 g, Distilled wa·

ter: 1000 mi). 0.2 mi of fungal cul- ture inoculated into broth and the respective inoculated broths were used for testing after incubation for 5 days at 25 C. The twofold serial dilucion technique was applied. A set of tubes containing only inocu lated broth was kept as controls.

After incubation for 5 days, the Iast tupe with no growth of the mic, roorganism was taken to repreSent the minimum inhibitory concentra tion (MIC, expressed in ,µg/ml).

The stock solution of the com·

pounds were prepared .in a:bsolute alcohol (3-6). Far that reason, the activity of ethyl alcohol against C.

albicans were tested· in- the samc dilutions and ethyl alcohol was found ·inactive. The antifungal acti vity of the compounds were given in Table !.

Determination of the parameters Regression analysis equations of the QSAR studies were perfor

ıned by using IBM-XT computer

\Vorking with Microstat Statistic Package. Parachor (P r) values oi- each compound w·ere calculated by the additive summation of the P values of all the atoms and the structural features using Qayle's Table (7). rı, ^{1T2 ,} 8, F, RMR and

M'\ıV values were taken from the table given by Hansch et al. (8).

These values were slıown in Table 2.

RESULTS

For QSAR studies, to design the best ·equations of 2-(p-substitu.

ted)-phenyl) oxazolo (4,5-b) pyridine derivatives, the antifungal acti.

vity against C. albicans was chosen as the biological activ:ity Some hydrophobic (rı, r), electronic (8, F, R) and steric (MR, MW, P,) pa.

rameters used as physicochemica]

constants for the quantitative structure-activity relationships ol these compounds. The lead optimi.

zation method has been examined by multiple regression analysis using the Microstat computer program. Log 1/C values were used in tlıe regression equations, where C 'was the molar concentrations of the MIC values of the compounds The data on the paramaters were stated in Table 2. The regression equations stated in Tables 4 and

tlıe parameters in the best equation

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Table 1 : Antifuı:ıg.U activity of 2-p-substituted-phenyl) oxazolo (4,5-b) pyridine derivatives agalnst C. albicans (MIC in p,g/ml)

(J( ^o ~~ o· ^h

^R

M M

Co

111> •

R c. alb ic:ans

no

1 CH

3 12.5

2 C.2. H 5 12.5

3

C <CH

3 >

3 25

4 OCH3 12.5

5 oc

1

H

5 12.5

6 NHı

12.5

7

NOa.

12.5

8

Cl

25

9 81"

25

(Table 3) were selected accorcling to the correlati~ matrix (Table 5) and the squares of their partial

regression coefficients. Observed and calculated values of !og 1/C were given in Table 6.

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Table 2 : The physiwcheınical parameters of 2-(p-suhstituted-phenyl) oxazolo {4,5·5) pyridine derivatives

Co~,

,_

"' ""

^p^c

'l[ 'lT

a

^5t 3l,

"'

1 0.56 'il.3136 -0.17 -0.04 -0.13 5.65 15.0 412.5 2 ı.ae 1.0404 -0. 15 -0.05 -0.10 10.30 29.1 452.5 3 1.98 3.9204 -0.20 -0.01 -0. 13 19.62 57. l 532.5 4 -0.02 0.ltt'04 -0.27 0.26 -0.51 7.67 31.4 443.4

'

^0.39 ^0.1444 ^-0.24 ^0.22 ^-0.44 ^12.47 ^{450 I} ^483.4

B -1.23 1.5129 -0.66 0.02: -0.69 5.42 16.0 403.2 7 -0.2a 0,0794 0,79 0.67 0. ıs 7.:36 4EL0 417.8

B 0.71 0.Sil<ll 0.23 0.41 -0, 15 6.03 35.4 415.9

•

^0.as ^0.7396 ^0,23 ^0.44 ^-0.17 ^a.aa ^79.9 ^428.7

Table 3 : Best equations geıu:rated for 2-(p-substituted-phenyl) oxazolo (4,5-b) pyrid.<ne derivatj\:es in C. albicans

log 1/C

0.0s<1s,:0.e0ssıMR • .:ı.a112

rı: 9 f( : ^ı 0.9605 s.ı lll.04 F: l4,59 0'<0.05)

C ıs "tha molar corıcentrat !ons of the MlC valueş of the col'fll'ounds. the nurnbers ın paranthesis ın the re9ression e",ı.ıations repre!.uıt the standart errors of the re9ress lon coeff ic ients, n ıs tha n1<mber of the corrı:ıounds, ^R² ^H th! S",\.lare of the rmılt!ple correlation coefficient, s is st3.nı:hrt de~latlon of tha re9ressıon and F Is tht F te:it fp.r tile si,.ı;lficance of the re9rasslon, P i;. th~ prob;ı.blltr

;f F tast.

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Table 4 : Regress!orı equations 5enerated for 2«p-substituted-phenyl) (4,5-b) uyricline d·2rivatives in C. albicans

Equ. No

1 og l/C

109 l/C

Equat ions

s: 0. 11 ; f: 3. 48

ı

-0.06(+0.05)'1T - 0,03(+0.04)'1T + 4.23 nr 9 ; - ~: 0.3939; - s: eı.12 ı F: 1.9Ş

.·

-0,05(t;0.06)'1İ - 0,IJ4C:!:0,05)'1Tl. - 0.07(;!:_0.H!)6' + 4.23 rı: 9: ~: e.4355; sı 0.12; F: 1.29

Jog l/C

l 09 J/C -0_,09<t0.07)'1\ - 0.0SC!0,05)'TT ^ı+ 0, 17(!0.23)d -0.46(H),37):'.Jli + 4.36

n: 9 ; R'-: eı.5892; s: 0,12; f: 1.43 5 log l/C -0.20(t0.03l'Tt - 0.l2(:!:0.02>ef + 0.32<teı.09lı::i'

-0.72(t0.14)2' + 0.04(+0,01) MR + 4.22 rı: 9 ; R'": 0.960S; s: 0.04; F: 14.5~

6 log l/C 0.0J<+0.02l ~ - 0.19(j:.0.37>ı1r' -0.06(!_0,24>d

~~·~⁰~!⁰·~~~.;s:s²~ ^s•^{0.14 ·} ^{F• 0.rs}

'"

^l/C ^-<ı.⁰¹^<^:!:.0.^e^{ı ı}^MR

^•

0.01(t0.39l1i' 0.08(t0.C:4l d + 4.25

o' ^s

'

^R~:^{0. 1151}

'

^s:0.15

,,

0.25

'"

^l/C ~e.0H:t0.0J) MR

-

0.08<±0.20) ~ 4.28 n :· 9

'

^R~:^0.1026

' "

^0.14

,,

0.34

9 l,09 l/C -0.01(!0.eıı MR

•

^4.25

o'

' ^'

R"": 0.0805

' "

^0.13

,,

_0.61

Table 5: Correlation matrix bet\veen regression parameters for substituted-phenyl) oxazolo (4,5-b) pyridinederivatives.

ı

"'

^uc ^"! ^er ^d

" ^"'

^MW ^~

'"

^l/C ^1.00

et -eı.sa l .00 crı· -0,5 ı 0,51 1.00

"

^{-0. 15} ^eı.14 ^-0.31 ^1.00

s; _-0.05 _{-0. 26} _-0.54 _{0 .ao:} _{J ,00}

ırı -0.20 0,48 0.01 <L83 0.3S 1.00 MR -0.28 0. 72 eı. 74 -0 .12 -0.34 0.13 l.00

""

^-eı.::ıa ^0.48 ^{0. 22} ^{0. 48} ^{0. 45} ^{0. 34} ^{0. 48} ^ı.⁰⁰

Pc -0 :2 l 0.70 0.66 -0 .20 ·-o, 37 0.04 0.88 0, 40 1.00

2-(p-

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Table 6: Antifunga.: t.ctivity of 2-(p-substituted-phenyl) oxazolo (4,5-b) pyridini'denvatives (h>g 1/C),

c ·o"1>'.·

>

No - ^Ob.^served

1 4.23

2 4,25·

3. 4.00

4 4.26

'5 4.28

6 . .4.23

7 4.29

a

3.97

..

9 4.04

-

.

DISCUS.SION

The antifunga~ activity of 2 (p substituted-phenyl) oxazolo-(4,5-b) pyridin derıivatives against. c~ albicans were .t·ested and · the compo·

unds were found significantly ac·

tive (MIC : 12,5-25µg/ml).

The multiple regression analy sis. results show that the act4vity aga:i-nst C. albicaris is fundamen- tally a function of the combinations of some. :. hydrophobic, electronic and steric pa:rameters. it is found that the parameters used alone do not show good correlations with the acfi.vity in the QSAR studies. The P value of the F-test for the best

Calcul ated Resid~al

- -·

.J'

4.24 -0.01

4.23 0.02

4.01 -0.01

..; ..

4.2~· 0.f:'l4 4.32

-

^-. -0.04-

.• ^.• .. . _..... .

4.23 -0.00

4.28 0.01

4.00 -0.03

4.02 . .. 0.02

.

equation is found less than 0.05 which shows us that the physicochemical parameters used as inde.

pendent variables are related to the dependent variable (log 1/C) in the multiple regression analysis, in addition, the standart deviati·

on(s) is minimized and foıward

elimiri'ation procedures, are stated in 6ur study (Table 4). These situa- dons are statistically justified the

·best equations given in Table 3 (9).

- The best equations which are .. obtained from the regression analy.

sis, involve 'iT,

7t2

va1ues as hydrophobic, S and F as e1'ectronic ancf MR as steric parameters. The

ô

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(sigma) and MR (Mo!ar Refracti.

vity) constants additive effect vitY.

are found having on biological acti.

The square of multiple regres.

&ion coefficient ^(R²⁾ were obtained for C. albicans as 0.9605. Thls me.

ans that the b~st equation which we have established can be ,used to predict the antifungal activity for untested 2-(p-substituted-phenyl) oxazolo (4,5-b) pyridines against C albicans. Of course, this obserVa tion supplies a lot of advantage:ı

in <lesigning the most active com pound.

REFERENCES

1 - Yalçın,

1.,

Şener, E., Özden, T.

«2 - (p - Sübstitüefenil) - Oksa zolo (4,5-b) Piridin Türevleri nin Sentez ve Yapı Açıklamala.

rı», Ankara Ecz. Fak. Der.

(15)1, 1985 (Baskıda).

2 - Yalçın,

1.,

Şener, E., Özden, S.

Akın, A., Yıldız, S., «2-(p-Sübs titüe-fenil) Oksazolo ^(4,S~b)Pi ridin Türevlerinin ^BazıGram (-) Bakterilere ^KarşıAntibak- teriyel .Etkileri ve Kantitatii Yapı-Etki İlişkileri», Ankara Ecz. Fak. Der., 1986 (Baskıda),

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.1.

Akın, A., Yıldız, S., «2-(p-Sübs.

titüe-fenil) Benzoksazol Türev- lerin-in Sentez, Yapı Aydınlat.

ması ve Mikrobiyoloji-k Etki.

si», FABAD J. Pharm. Scı.,I 1986 (Baskıda).

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Özden, T., Akın, A., Yıldız, S.,

«Synthesis and Microbiologi:Cal Aotivities of 5-Amino-2-(p-Subs,

tituted-pheızyl) Benzoxaı;alo

Deri.vatives», ^DoğaBilim Der- gisi, C, 1986 (Baskıda).

5 - ·Schraufstatter, E., «Schwer- metallkomplexbildung und an- tibakterielle Wirki.ıng», Zeit- schrift Für l'-Taturforschung, 5b, 190-195, 1950.

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Chimica Therapeutica, 5, 435.

438, 1979.

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8 - Hansch, C., Leo, A., Unger, S.H., Kim, K.H., Nikait;uıi,_ D., Lier, E.J., «Aromatic Substi-

tuent Constants for Structure- Activity Corielıations>), J. Med.

Chem., 16 ^(il), 1207, 1973.

9 - Chu, K.C., «The Quantitative Analysis of Structure-Activity

Re~ationships», Burg·er's Me- tlicinal Chemistry, New York, John Wiley and Sons Ltd., Vol I, 406, 1980.

The Antifungal Activity Of 2-(p-Substituted-Phenyl)Oxazolo (4,5-b)Pyridine derivatives Against

The Antifungal Activity Of 2-(p-Substituted-Phenyl)Oxazolo (4,5-b)Pyridine derivatives Against

Candida Albicans And The Quantitative Structure • Activity

Relationsh i ps

o,

(J( o ~~ o· h

M M

Co

R c. alb ic:ans

no

1 CH

3 12.5

2 C.2. H 5 12.5

C <CH

3 >

3 25

4 OCH3 12.5

5 oc

H

5 12.5

12.5

7

12.5

8

25

25

,_

"' ""

a

"'

'

•

'"

•

'

'

,,

'"

-

'

' "

,,

•

' '

' "

,,

"'

" "'

'"

"

""

c ·o"1>'.·

a

-

-

.

7t2

ô

1.,

1.,

.1.

~

(J( ^o ~~ o· ^h

^•

' ^'

" ^"'