f
ıFABAD J. Pharm. Sci., 27, 85-87, 2002
RESEARCH ARTICLES / BİLlMSEL ARAŞTIRMALAR
Evaluation of Antimicrobial Activities of Some Dioxolane Derivatives
Ahu GÜNEY*, Fügen ÖZKANLI*0, Ünsal ÇALIŞ*, Meral ÖZALP**
Evaluation of Aııtiınicrobial Activities of Some Dioxolane Derivatives
Srun11ıary : in tlıis study antibacterial and antifungal activ- ities of the synthesized ten dioxolane derivatives wlıich con- tain azole and condensed azole ring in tlıeir structure were determined against 4 bacteria, 2 of thenı are Gram-positive (Staphylococcus aureus ATCC 25923, Enterococcus faecalis ATCC 29212) and 2 oftlıenı are Granı-negative (Escherichia cali ATCC 25922, Pseudonıonas aeruginosa ATCC 27853) and 3 veast-like fungi (Candida albicans ATCC 90028, Can- dida krusei ATCC 6258 and Candida parapsilosis ATCC 22019). The activities of tlıe conıpounds were deternıined by
tlıe brot/ı nıicrodilution nıethod and Ceftazidinıe and Flu- conazole were ıısed as standards. Conıpoıınd 9 and 10 showed activity (4 µg/nıl) against S. aureus, conıpound 1 and 4 slıowed activity ( 32 µg/1111) against C. krusei, compound 1 (8
µg/nıl) and conıpound 6 ( 4 µg/nıl) slıowed activity against C.
albicans.
Key Words: Dioxolane, antibacterial activity, antifııngal
activity, antinıicrobial activity Received
Revised Accepted
15.4.2002 10.6.2002 14.6.2002
INIRODUCTION
Antifungals (antirnycotics) are substances used far the treatrnent of fungal infections. Initial ınajor
progress in the therapy of rnycoses was rnade in the l960's with the introduction of the polyene anti- rnycotics Flucytosine and Griseofulvin of rnajor iın
portance, and later with the developrnent of anti- fungals of the azole type. These substances as wide spectrurn antifungals, are effective in a variety of fun- gal infections of a wide range and have therefore re- placed rnany older substances.1-4
Bazı J)ioksola11 Türevlerinin Anti11ıikrobiyal Aktivitelerinin
Değerlendirilnıesi
Öıet4J}~t çalıivn_1ada sentezleri daha önceden yaprlan, azal ve kondanse -azal halkaları--içer~n _djpksolan türevi on tane
bileşiğin ikisi Granı-positif (StaphylöcoCcus aureus ATCC 25923, Enterococcus faccalis ATCC 29212) ve ikisi Granı
negatif (Escherichia coli ATCC 25922, Pseudonıonas ae- ruginosa ATCC 27853) olnıak üz.ere toptanı 4 bakteri ve 3
ınaya benzeri fııngusa (Candida albicans ATCC 90028, Can- dida krusei ATCC 6258 ve Candida parapsilosis ATCC 22019) karşı antibakteriyel ve antiftıngal etkileri in-
celennıiştir. Bileşiklerin aktiviteleri nıikrodiliisyon yön-
tenıiyle tayin edilnıiş ve Ceftazidinı.e ve Fluconazole standart olarak kullanıbnıştır. Bileşik 9 ve 10, S. aureus'a karşı (4 µg/111.l) etkili bulunurken bileşik 1 ve 4, C. krusei'ye karşı
(32 µg/nıl), bileşik 1 (8 µglml) ve bileşik 6 (4 µglml) ise C.
albicans'a karşı aktif bıılunnıu\Hur.
Anahtar kelimeler : Dioksolan, antibakterivel aktivite, an- tifungal aktivite, anti/nikrobiyal ak- tivite.
1-Substitue-lH-azoles represent a relatively new class of versatile antifungal agents with an apparently unique rnechanisrn of action. The properties of early rnernbers of the class, such as Clotriınazole and Mi- conazole, were reported independently in 19695.
Clotrimazole
Örrn2-GI-O-GI2-0-0
a-Q a-
a
Miconazole
* Hacettepe University, Faculty of Pharmacy, Department of Pharmaceutical Chemistry, 06100, Ankara TURKEY.
** Hacettepe University, Faculty of Pharmacy, Department of Pharınaceutical Microbiology, 06100, Ankara TURKEY.
°
Correspondence85
Güney, Özkanh, Çalış, Özalp
in general, 1-substitue-lH-azoles are effective against most fungi that cause superficial infections of the skin and mucous membranes, including the dermatophytes, such as Trichophyton, Epi- dermophyton, Microsporum and yeasts such as Can- dida albicans.4-8
The primary structural requirement for members of this class is a weakly basic imidazole (or azole) ring bonded by nitrogen-carbon linkage to the remainder of the molecule. 5,9 On the other hand it was reported that some dioxolane derivatives had remarkable anti- microbial activity. 10 Regarding this fact, these azole containing antimicrobial drugs have prompted us to study some arylalkylazoles having dioxolane group as the alkylene bridge between aryl group and~azqle
ring.
.A
R: Imidazole, pyrlı.zole, 1,2,4-triazole, benzimidazole, benzotriazole R': -H, -CH; A: HCI (Compound 1-4,6-9)
EXPERIMENTALPART
Minimal inhibitory concentrations (M!Cs) were de- termined by broth microdilution following the pro- cedures recommended by the National Committee for Clinical Laboratory Standardsll,12• Two Gram- positive (Staphylococcus aureus ATCC 25923, En- terococcus faecalis ATCC 29212) and two Gram- negative (Escherichia cali ATCC 25922, Pseııdo
manas aenıginasa ATCC 27853) bacteria were used as quality control strains. For testing antifungal activ- ities of the compounds, these reference strains were tested: Candida albicans ATCC 90028, Candida kru- : sei ATCC 6258 and Candida parapsilosis ATCC 22019.
Mueller-Hinton broth (Difco Laboratories, Detroit, · MI, USA) was used when testing bacterial strains.
For Candida species, RPMI-1640 medium with L- glutamine, buffered with MOPS (ICN, FLOW; Au- rora, OH, USA) was used. The inoculum densities 86
were 5xıos cfu/ml and 0.5-2.5x103 cfu/ml for bac- teria and yeasts, respectively. The test compounds were dissolved in 100 % dimethylsulfoxide (it was
· not observed !hat DMSO had no inhibitor effect on the microorganisms studied) and the final two-fold concentrations were prepared from 512 µg/ml to 0.5 µg/ml. Ceftazidime and fluconazole (from the re- spective manufacturers) were used as reference anti- biotics for bacteria and yeasts, respectively. The dou- bling concentrations used for both were 64 µg/ml to 0.0625 µg/ml.
For bacteria, M!Cs were determined after incubation for 24 hat 35 °C and for fungi 48 hat 35 °C. Minimal inhibitory concentrations were defineci as the lowest concentrations of the antimicrobial agents that in- hibited visible growth of the microorganisms.
RESULTS AND DISCUSSION
The synthesis and structural elucidation of !he com- pounds were published in our previous study13. All the compounds were tested for in vitro antimicrobial activity by the microdilution method. The MIC values of the compounds against some pathogenic baçteria
(Staplıylococcus aııreııs ATCC 25923, Enterococcus faecalis ATCC 29212, Escherichia cali ATCC 25922 and Pseudomonas aerııginasa ATCC 27853) and yeasts like fungi (Candida albicans ATCC 90028, Candida krusei ATCC 6258 and Candida parapsilosis ATCC 22019) are presented in Tables 1 and 2.
The antibacterial activity results of the compounds against Gram-positive and Gram-negative bacteria are shown in Table 1. According to the values, Com- pound 9 and 10 were the most active compounds ( 4 µg/ml) against S. aııreus. it was observed that Com- pouµd 9 was the most active against E. faecalis.
The results of screening for antifııngal activity of
compm.ınds are reported in Table 2. Examination of the dala in the table revealed !hat compounds 1 and 4 were found as effective as fluconazole against C. kru-
·. sei (32 µg/ml). On the other hand Compound 6 was alsa found to be !he most active compound against C.
albicans (4 µg/ml). Compounds 1, 5, 8 were more ef-
FABAD J. Pharm. Sci., 27, 85-87, 2002
fective against C. albicans. It was observed that com·
pounds 6, 9 and 10 were more effective than the oth·
er compounds against C. parapsilosis. In view of an·
timicrobial activity results, we assume that com·
pounds 1,5,6,9 and 10 are the most significant com·
pounds in the series.
Fiı1ally, !his study suggests that antifungal activities of dioxolane derivatives are more effective than their antibacterial activities.
Acknowledgements
This work was supported by Hacettepe University Research Fund (Projeci number 98.01.301.003)
Table 1: Antibacterial activity results of the tested compounds (MIC µg/ml)
S.aureus E.faecal~ E.corı P .aeııtjnosa
Compourds (ATCC25923) (ATCC29212) (ATCC25922) (ATCC27853)
1 64 128 128
2 128 128 128
3 256 128 256
4 256 512 256
5 256 128 256
6 32 128 256
7 256 128 256
8 128 128 256
9 4 16 256
10 4 128 256
Ceftazidime 16 • 0.5
' : No acti~ty was observed against E. faecalis.
Table 2: Antifungal activity results compounds (MIC µg/ml) Compounds C.albicans C.krusei
Compounds (ATCC 90028) (ATCC 6258)
1 8 32
2 128 128
3 128 128
4 128 32
5 16 64
6 4 64
7 128 128
8 32 128
9 128 64
10 128 128
Fluconazole 1 32
256 128 128 512 512 512 512 256 256 256 4
of the tested
C.parapsilosis (ATCC 22019)
64 128
64 64 64 32 64 64 32 32 8
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