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ORIGINAL ARTICLE/ARTICLE ORIGINAL
Synthesis and fungistatic activity of aryl aldoxime derivatives ` se et activite ´ fongistatique des de ´ rive ´ s d’aryle aldoxime Synthe W. Marek Gołe ˛biewski *, M. Cyrta, A. Michalczyk Institute of Industrial Organic Chemistry, Annopol 6, 03-236 Warsaw, Poland Received 19 August 2014; received in revised form 9 October 2014; accepted 30 October 2014
KEYWORDS Fungicides; Oxime ethers; Oxime esters; Dermatophytes; Lipophilicity
MOTS CLÉS Fongicides ; Éthers d’oximes ; Esters d’oximes ; Les dermatophytes ; La lipophilie
Summary Objective. — The antifungal activity of 13 arylaldoxime ester and ether derivatives was tested against 4 dermatophytes Trichophyton mentagrophytes (TM), Microsporum canis (MC); M. cookei, and M. gypseum. Materials and methods. — Structures of all new compounds prepared from aryl aldehydes were established by spectral means. The tests were performed on the Sabouraud Dextrose Agar (SDA) substrate. The sensitivity of the dermatophyte strains towards oxime derivatives was established by determining MIC and MFC values. Results. — The tested compounds showed a moderate fungicidal activity reaching 100% inhibition rate at 1% concentration. The activity against M. canis of 4 derivatives was higher than the activity of a reference drug clotrimazole. Conclusion. — A novel group of biologically active compounds was introduced. Simple aldoxime derivatives can be developed into a new class of antifungals. # 2014 Elsevier Masson SAS. All rights reserved. Résumé Objectif. — L’activité antifongique des 13 esters et éther dérivés d’arylaldoxime a été testée contre 4 dermatophytes Trichophyton mentagrophytes, Microsporum canis, M. cookei, et M. gypseum. Mate´riels et me´thodes. — Les structures de tous les nouveaux composés préparés à partir d’aldéhydes aryliques ont été établies en utilisant des méthodes spectrales. Les essais ont été réalisés sur le substrat de Sabouraud Dextrose Agar (SDA). La sensibilité des souches de dermatophytes vis à vis des dérivés d’oxime a été établi par le calcul des valeurs de MIC et MFC.
* Corresponding author. E-mail address: [email protected] (W. Marek Gołe ˛biewski). http://dx.doi.org/10.1016/j.mycmed.2014.10.026 1156-5233/# 2014 Elsevier Masson SAS. All rights reserved.
Please cite this article in press as: Marek W, et al. Synthesis and fungistatic activity of aryl aldoxime derivatives. Journal De Mycologie Médicale (2014), http://dx.doi.org/10.1016/j.mycmed.2014.10.026
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W. Marek Gołe ˛biewski et al. Re ´sultats. — Les composés testés ont montré une activité fongicide modérée pour atteindre le taux d’inhibition de 100 % à une concentration de 1 %. L’activité contre M. canis de 4 dérivés était supérieure à l’activité du clotrimazole, le médicament de référence. Conclusion. — Un nouveau groupe de composés biologiquement actifs a été présenté. Des dérivés simples d’aldoxime peuvent être développés comme nouvelle classe de composés antifongiques. # 2014 Elsevier Masson SAS. Tous droits réservés.
Introduction
Material and methods
Biological activity of Schiff bases derived from aromatic carbonyl compounds is known. Several benzo-1,3-dioxolealdoxime ethers show pyrethrum synergist activities against test Tribolium castaneum insect [23]. Alpha-azolylmethylalpha-aryl-substituted benzaldoxime derivatives display fungicidal activity against the Candida strains causing infections in humans and other animals [17]. Vanillin oxime-alkanoates showed in vitro antifungal activity against three phytopathogenic fungi Macrophomina phaseolina, Rhizoctonia solani and Sclerotium rolfsii, which was significantly higher than that of vanillin or its oxime. We have been interested in synthesis and properties of aryl aldehydes Schiff bases for some time. Several salicylaldehyde hydrazones showed a moderate fungicidal and bactericidal activity [5]. The aldoxime derivatives were a subject of our recent patent application [6] concerning antifungal activity against plant pathogens. There is a continuous need for new selective protection agents due to appearance of growing pathogens resistance. In continuation of our work on aryl aldehydes Schiff bases we undertook the synthesis of new oxime derivatives as potentially biologically active compounds. Herein, we present results of our research on preparation and biological screening of several aryl aldoxime ethers and esters against dermatophytes Trichophyton mentagrophytes (TM), Microsporum canis (MC); M. cookei, and M. gypseum (MG). T. mentagrophytes and M. canis are zoophilic fungal species infecting skin, hair and nails. M. cookei and M. gypseum are geophilic fungal species of a worldwide distribution, which cause skin infections in animals and humans, particularly children and rural workers during warm humid weather. Dermatophytoses are most often treated with the imidazole derivatives such as clotrimazole, ketoconazole, bifonazole, econazole, miconazole or triazole derivatives such as fluconazole, itraconazole, which interfere with fungal ergosterol synthesis by inhibiting lanosterol 14-demethylase [14,22]. These strong systemic antifungal drugs are usually effective to cure the disease, but they often have side effects, growing pathogen resistance is observed and more immunosuppressed patients are at risk for these infections. Other frequently applied drugs include griseofulvin (spirocyclohexenodione derivative), allylamine derivatives (terbinafine), [8], short and medium-chain fatty acids such as formic, propionic, lactic, tartaric and citric acids [19], thiazole derivatives [2], 1,3,4-thiadiazole derivatives [13], dihaloquinolinols [3,4] or simple sodium pyrithione (sodium 2pyridinethiol-1-oxide) [15]. The other agents are derivatives of natural quartenized polysaccharide chitosan [18], essential oils and various organic extracts [1,20].
Test organisms Fungi T. mentagrophytes ATCC 9533, M. gypseum ATCC 6231, M. cookei ATCC 13275 were obtained from American Type Culture Collection (ATCC collection). The test strains were maintained on Sabouraud’s Dextrose Agar (SDA) (Oxoid, UK) slants of pH 5.6, were stored in refrigerator at 4 8C and were transferred every 6—8 weeks to a fresh medium.
Fungicidal testing Determination of minimum inhibitory concentration (MIC) and minimum fungicide concentration (MFC) for dermatophytes The aim of this experiment was to determine the sensitivity of fungi to various concentrations of the test compounds and to determine the minimal concentrations (MIC) of the test compounds which completely inhibit the visible growth of fungi on the agar medium and to find the minimal fungicidal concentrations (MFC) values which kill 100% of a particular fungus. The test was performed on the Sabouraud Dextrose Agar (SDA) substrate in concentration range from 0.25% to 2%. Acetone solutions of test compounds were applied in an amount of 1 mL to the surface of agar-solidified medium on Petri dishes and then uniformly distributed and allowed to evaporate the solvent under aseptic conditions. Thereafter, the plates were loaded with mycelial discs (5 mm diameter) cut from homogeneous 5—7-day-old cultures of fungi grown on a SDA medium. As a control acetone was applied to the agar medium followed by mycelia discs after evaporation of acetone. The test was performed in three replications. As a reference, clotrimazole was used. As the value of minimum inhibitory concentration (MIC) the concentration of a compound limiting the fungus colony growth to 7 mm, i.e. 2 mm beyond the diameter of the incorporated inoculum, was adopted. Fungal inocula considered as negative (no growth) in the MIC test were incorporated into solid medium (SDA) without the addition of the test compounds and were incubated at the optimum temperature and time for the growth of the test fungi. As the value of the minimum fungicidal concentration (MFC), the concentration of compound causing total lack of growth of a fungus (macroscopic evaluation) was adopted.
Synthesis of tested compounds Reagent grade chemicals were used without further purification unless otherwise noted. Spectra were obtained as follows: IR spectra on a JASCO FTIR-420 spectrometer, 1H NMR
Please cite this article in press as: Marek W, et al. Synthesis and fungistatic activity of aryl aldoxime derivatives. Journal De Mycologie Médicale (2014), http://dx.doi.org/10.1016/j.mycmed.2014.10.026
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Synthesis and fungistatic activity of aryl aldoxime derivatives spectra on a Varian 200 UNITY plus 200, spectrometer in deuterated chloroform. Chemical shifts are given in ppm (d) relative to TMS as an internal standard, coupling constants are reported in Hz. EI mass spectra were run on a AMD M-40, HR EI mass spectra on a AMD 604. The octanol/water partition coefficients (clogP) were calculated using the computer program Hyperchem 7.5.
Typical procedure for synthesis of oxime ethers 3a, 4a A solution of oxime 2a (0.86 g, 4.75 mmol), DMSO (7 mL), pentyl bromide (4.3 g, 28.5 mmol), and potassium hydroxide (2.8 g) in ethanol (9 mL) was stirred at room temperature for half an hour. Then, brine was added (15 mL) and the mixture was extracted with ethyl acetate. The organic layer was washed with brine. After drying over anhydrous MgSO4, the solvent was evaporated under vacuum. The product was obtained as a yellow oil 0.55 g (46%). IR (neat) 2932, 1607, 1511, 998, 834 cm1; 1H NMR (CDCl3, 200 MHz) d 8.03 (s, 1H, HC = N), 7.51 (d, J = 9.0 Hz, 2H, H-2,6), 7.03 (d, J = 9.0 Hz, 2H, H-3,5), 5.19 (s, 2H, O-CH2-O), 4.14 (t, J = 6.6 Hz, 2H, O-CH2-CH2), 3.48 (s, 3H, OCH3), 0.92 (m, 3H, CH3). EI MS m/z (%of intensity) 251 (60), 250 (23), 220 (60), 192 (46). HR EI MS calcd. for C14H21NO3: 251.1521, found: 251.1527.
Typical procedure for synthesis of oxime ethers 5a—f A mixture of oxime 2a (0.4 g, 2 mmol), DMSO (3 mL), ethyl bromoacetate (0.5 mL, 4.95 mmol) and potassium carbonate
3 (3 g) in water (2 mL) was stirred at room temperature for 18 h. Then, 20 mL of brine was added and the solution was extracted with ethyl acetate. After drying over anhydrous MgSO4, the solvent was evaporated under vacuum. The product was obtained as a yellow oil 0.3 g (75%). IR (KBr) 2932, 1754, 1606, 1510, 1152, 999, 836, 532 cm1. 1H NMR (CDCl3, 200 MHz) d 8.16 (s, 1H, HC = N), 7.52 (d, J = 8.8 Hz, 2H, H-2, 6), 7.02 (d, J = 8.8 Hz, 2H, H-3, 5), 5.20 (s, 2H, OCH2O), 4.69 (s, 2H, OCH2C = O), 4.25 (q, J = 7.2 Hz, 2H, OCH2CH3), 3.48 (s, 3H, OCH3), 1.29 (t, J = 7.2 Hz, 3H, CH3). EI MS m/z (%) 267 (75), 137 (20), 164 (21), 134 (20). HR EIMS calc. for C13H17NO5: 267.11067; found: 267.11076.
Typical procedure for synthesis of oxime esters 6e and f A solution of the oxime 2e (0.78 g, 4.1 mmol) and triethylamine (0.41 g, 4.1 mmol) in methylene chloride (20 mL) was stirred at 0 8C for 5 minutes. Then, a solution of crotonoyl chloride (0.82 mL, 4.1 mmol) was added and the solution was stirred for 20 hours. After this time, the reaction mixture was washed successively with 10% cold acetic acid (5 mL), 10% sodium carbonate (5 mL), brine and water. Product was obtained as a white solid 0.72 g (68%). IR (KBr) 1753, 1654, 1584, 1475, 1387, 1296, 1141, 1091, 986, 826 cm1; 1 H NMR (CDCl3, 200 MHz) d 8.78 (s, 1H, HC = N), 7.62 (d, J = 8.4 Hz, 1H, H-60 ), 7.55 (d, J = 1.8 Hz, 1H, H-30 ), 7.42 (qd, J = 15.8; 1.9 Hz, 1 H, H-3), 7.38 (dd, J = 8.4; 1.9 Hz, 1H, H50 ), 5.97 (dd, J = 15.8; 1.9 Hz; 1H, -CH = CH-), 1.97 (dd, J = 7.0; 1.9 Hz, 3H). EI MS m/z (%) 173 (17), 171 (23), 147 (20), 136 (31). HR EI MS, calc. for C11H9Cl2NO2: 257.0010; found: 257.0018.
Scheme 1 Synthesis of oxime ethers and esters 3—6. i: NH2OH HCl, NaOH, rt, 10 h; ii: AlkBr, KOH, DMSO-H2O, rt, 0.5 h; iii: BrCO2Et, K2CO3, DMSO, rt, 18 h; iv: MeCH = CHCOCl, NEt3, CH2Cl2, 0 8C > rt, 20 h. ´ rature ambiante, 10 h ; ii : AlkBr, KOH, DMSO-H2O, ` se des ´ethers et des esters 3—6 d’oxime. i : NH2OH HCl, NaOH, tempe Synthe ´ rature ambiante, 18 h ; iv : MeCH = CHCOCl, NEt3, CH2Cl2, ´ rature ambiante, 0,5 h ; iii : BrCO2Et, K2CO3, DMSO, tempe tempe 0 8C > rt, 20 h. Please cite this article in press as: Marek W, et al. Synthesis and fungistatic activity of aryl aldoxime derivatives. Journal De Mycologie Médicale (2014), http://dx.doi.org/10.1016/j.mycmed.2014.10.026
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Table 1 Antifungal activity of oxime ethers and esters against dermatophytes. ´ antifongique des ´ethers et des esters d’oxime contre les dermatophytes. Activite Number
Compound/clog
5e
N O CH2 -COOEt
Microsporum canis
Microsporum gypseum
Microsporum cookei
Trichophyton mentagrophytes
MIC (%)
MFC (%)
MIC (%)
MFC (%)
MIC (%)
MFC (%)
MIC (%)
MFC (%)
1
1.5
1
1
1.5
1.5
1
1.5
2
>2
1.5
1.5
2
2
0.5
1.5
>2
>2
1
1.5
1.5
1.5
1.5
1.5
1.5
2
1
1.5
1
1.5
1
>2
2
>2
1.5
1.5
1.5
1.5
1.5
2
1.5
2
1.5
1.5
1
1
1.5
2
2
>2
2
2
>2
>2
>2
>2
>2
>2
2
2
>2
>2
>2
>2
>2
>2
2
2
>2
>2
2
>2
2
>2
1.5
1.5
1.5
>2
1.5
2
Cl
4.46 Cl
5f
N O CH2-COOEt
3.98 CF 3
5c
N O CH2-COOEt OMOM
3.02
Cl
5d
N O CH2-COOEt
4.35
5a
N O CH2-COOEt
2.53 OMOM
5b
N O CH2-COOEt OMOM
2.13
3c
N O C 2H5 OMOM
2.92
Cl
4c
N O C 5H11 OMOM
4.51
Cl
4e
N
O
C5H 11
Cl
5.96 Cl
3a
N O
C2 H5
2.43 OMOM
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Table 1 (Continued )
Number
Compound/clog
4a
N O
C5H11
Microsporum canis
Microsporum gypseum
Microsporum cookei
Trichophyton mentagrophytes
MIC (%)
MFC (%)
MIC (%)
MFC (%)
MIC (%)
MFC (%)
MIC (%)
MFC (%)
>2
>2
1.5
2
2
2
>2
>2
1.5
2
0.25
1
1
1
1.5
2
2
>2
1
1.5
0.5
1
1
2
2
2
< 0.25
0.25
< 0.25
< 0.25
< 0.25
< 0.25
4.03 OMOM
6f
N O COCH=CHCH3
4.09 CF3
6e
N O COCH=CHCH 3 Cl
5.02 Cl
Clotrimazole a
Minimal inhibitory concentration (MIC) is the lowest concentration of an antimicrobial that will totally inhibit the visible growth of a microorganism. Minimal fungicidal concentration (MFC) is the lowest concentration of an antifungal agent required to kill 100% of a particular fungus. a Reference compound.
Results and discussion Synthesis of the title compounds is outlined on Scheme 1. In the hydroxysubstituted starting benzaldehydes the OH group was protected as a methoxymethyl (MOM) ether using P2O5 catalyzed acetal exchange reaction with dimethoxymethane in chloroform in the presence of diisopropylethylamine [7] rather than an older procedure with carcinogenic chloromethyl methyl ether. Some pyrrole derivatives with 1-MOM substituents showed biological activity [9]. The aldehydes 1a—1f were then converted to the oximes with hydroxylamine hydrochloride and aqueous sodium hydroxide. E configuration of the oximes was determined on the basis of chemical shift values of HC = N proton in 1H NMR spectra above 8.0 ppm [12,16,21]. We have performed arylaldehyde oxime alkylation with simple alkyl bromides in the presence of aqueous-DMSO solutions of potassium hydroxide following the published procedure [11]. On the other hand, oxime alkylation with ethyl bromoacetate was carried out in aqueous-DMSO solutions of potassium carbonate. Exemplary deprotection of the MOM group was smoothly performed for ether 3a with a methanolic solution of hydrochloric acid by modification of the published procedure [24]. Oximes were acylated with an acyl chloride in dichloromethane in the presence of triethylamine as a base.
Biological activity and structure activity relationship The obtained oxime derivatives were evaluated in vitro against dermatophytes T. mentagrophytes (TM), M. canis
(MC); M. cookei, and M. gypseum. The results shown in Table 1 indicate diverse antifungal activity. In comparison to the reference compound, clotrimazole, the acetates 5e, 5d, and 5b as well as the crotonate 6f were more effective against M. canis. However, against the other examined pathogens clotrimazole showed at least for times higher activity than the described oxime derivatives. The synthesized oxime derivatives can be classified into three groups differing in phenyl ring and oxime part substituents. Compounds from the first group are benzaldoxime acetates 5a—f. Four ethers from this group 5b, 5d—f showed moderate activity against T. mentagrophytes (TM), M. cookei, and/or M. gypseum fungal strains (Table 1). The second group includes five simple benzaldoxime alkyl ethers 3a, 3c, 4a, 4c, 4e. One of them, ether 3a displayed a moderate inhibitory activity against T. mentagrophytes (TM) and M. gypseum fungal strains. Compounds from the third group are most active benzaldoxime esters 6f and 6e showing relatively good potency against respectively, M. cookei, and M. gypseum fungal strains. Analyzing structure activity relationship for the obtained esters generally derivatives with electron-withdrawing groups (EWG) showed higher fungicidal activity than esters with electron-donating groups (EDG) (compare 5e and 5f to 5a and 5d). In the first group, the activity was higher for 5e than for 5f with a weaker EWG character. Comparison of the moderate displayed fungicidal activity with the other groups of compounds showed that oxime derivatives were more potent than organic acids (MIC of ca. 5% or 50,000 mg/mL) [19]. However, the other classes of antifungal compounds in clinical use exhibit higher activities. Terpenoid quinines show MIC against T. mentagrophytes
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of 2—50 mg/mL [8], azoles show MIC in the range 1—64 mg/ mL [14,17], triazoles display MIC of ca. 8 mg/mL and quartenized chitosan derivatives exhibit MIC in the range 125— 1000 mg/mL [18]. Mechanism of fungicidal activity was well established for azole fungicides. For this group of compounds it involves interaction with membrane-bound enzyme, fungal lanosterol 14a-demethylase [17], which is part of the ergosterol biosynthetic pathway. The resulting ergosterol decrease renders fungal cells vulnerable to further membrane damage. Similarly in case of a quite different group of potential fungistatic agents, organic acids, the main targets are cell walls and membrane proteins [19]. Mechanism of quaternized chitosan derivatives against fungi remains debatable, but generally, it is attributed to a formation of polyelectrolyte complex between positively charged quaternary ammonium salts and negatively charged cell walls of fungi leading to cell wall disruption [18]. In light of the above data it can be tentatively assumed that described here oxime derivatives interact also with fungal wall enzymes. The antifungal activity can be correlated with lipophilicity of the oxime derivatives measured by the logarithm of octanol-water partition coefficient clogP [10]. Unfortunately no simple dependence was found between the calculated clogP values and the biological activity. However, the optimal ranges of clogP as a measure of lipophilicity of the synthesized benzaldoxime derivatives could be discerned. For the most active against M. canis oxime acetate derivative 5e, 5d clogP fell in the range of 4.0—4.5. In case of compounds most active against M. cookei the optimal ranges of lipophilicity corresponded to clogP of 2.0—2.5 (6f, 5b) and 4.0—4.5 for acetate with strongly electron-withdrawing substituents 5e. For compounds most potent against M. gypseum (6e, 6f, 5b, 5d) and T. mentagrophytes (5f, 5e) the advantageous ranges of lipophilicity were those with clogP values of 2.0—2.5 and 4.0—5.0.
Conclusions Several new aryl aldoxime ethers and esters have been prepared. The obtained compounds characterized by spectroscopic data (IR, 1H NMR and MS) showed a moderate antifungal activity particularly against dermatophytes T. mentagrophytes (TM), M. cookei. The observed biological potency showed some correlation with the lipophilicity of the compounds measured by octanol-water partition coefficient clogP. Based on the obtained results syntheses of new, more potent derivatives could be envisaged. Research is in progress to enhance the biological activity of the Schiff base type derivatives.
Disclosure of interest The authors declare that they have no conflicts of interest concerning this article.
Acknowledgements This work was supported in part by the Polish Ministry of Science and Higher Education (Grant 429/E-142/2013) which is gratefully acknowledged.
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MYCMED-527; No. of Pages 7 Journal de Mycologie Médicale (2014) xxx, xxx—xxx
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ORIGINAL ARTICLE/ARTICLE ORIGINAL
Synthesis and fungistatic activity of aryl aldoxime derivatives ` se et activite ´ fongistatique des de ´ rive ´ s d’aryle aldoxime Synthe W. Marek Gołe ˛biewski *, M. Cyrta, A. Michalczyk Institute of Industrial Organic Chemistry, Annopol 6, 03-236 Warsaw, Poland Received 19 August 2014; received in revised form 9 October 2014; accepted 30 October 2014
KEYWORDS Fungicides; Oxime ethers; Oxime esters; Dermatophytes; Lipophilicity
MOTS CLÉS Fongicides ; Éthers d’oximes ; Esters d’oximes ; Les dermatophytes ; La lipophilie
Summary Objective. — The antifungal activity of 13 arylaldoxime ester and ether derivatives was tested against 4 dermatophytes Trichophyton mentagrophytes (TM), Microsporum canis (MC); M. cookei, and M. gypseum. Materials and methods. — Structures of all new compounds prepared from aryl aldehydes were established by spectral means. The tests were performed on the Sabouraud Dextrose Agar (SDA) substrate. The sensitivity of the dermatophyte strains towards oxime derivatives was established by determining MIC and MFC values. Results. — The tested compounds showed a moderate fungicidal activity reaching 100% inhibition rate at 1% concentration. The activity against M. canis of 4 derivatives was higher than the activity of a reference drug clotrimazole. Conclusion. — A novel group of biologically active compounds was introduced. Simple aldoxime derivatives can be developed into a new class of antifungals. # 2014 Elsevier Masson SAS. All rights reserved. Résumé Objectif. — L’activité antifongique des 13 esters et éther dérivés d’arylaldoxime a été testée contre 4 dermatophytes Trichophyton mentagrophytes, Microsporum canis, M. cookei, et M. gypseum. Mate´riels et me´thodes. — Les structures de tous les nouveaux composés préparés à partir d’aldéhydes aryliques ont été établies en utilisant des méthodes spectrales. Les essais ont été réalisés sur le substrat de Sabouraud Dextrose Agar (SDA). La sensibilité des souches de dermatophytes vis à vis des dérivés d’oxime a été établi par le calcul des valeurs de MIC et MFC.
* Corresponding author. E-mail address: [email protected] (W. Marek Gołe ˛biewski). http://dx.doi.org/10.1016/j.mycmed.2014.10.026 1156-5233/# 2014 Elsevier Masson SAS. All rights reserved.
Please cite this article in press as: Marek W, et al. Synthesis and fungistatic activity of aryl aldoxime derivatives. Journal De Mycologie Médicale (2014), http://dx.doi.org/10.1016/j.mycmed.2014.10.026
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W. Marek Gołe ˛biewski et al. Re ´sultats. — Les composés testés ont montré une activité fongicide modérée pour atteindre le taux d’inhibition de 100 % à une concentration de 1 %. L’activité contre M. canis de 4 dérivés était supérieure à l’activité du clotrimazole, le médicament de référence. Conclusion. — Un nouveau groupe de composés biologiquement actifs a été présenté. Des dérivés simples d’aldoxime peuvent être développés comme nouvelle classe de composés antifongiques. # 2014 Elsevier Masson SAS. Tous droits réservés.
Introduction
Material and methods
Biological activity of Schiff bases derived from aromatic carbonyl compounds is known. Several benzo-1,3-dioxolealdoxime ethers show pyrethrum synergist activities against test Tribolium castaneum insect [23]. Alpha-azolylmethylalpha-aryl-substituted benzaldoxime derivatives display fungicidal activity against the Candida strains causing infections in humans and other animals [17]. Vanillin oxime-alkanoates showed in vitro antifungal activity against three phytopathogenic fungi Macrophomina phaseolina, Rhizoctonia solani and Sclerotium rolfsii, which was significantly higher than that of vanillin or its oxime. We have been interested in synthesis and properties of aryl aldehydes Schiff bases for some time. Several salicylaldehyde hydrazones showed a moderate fungicidal and bactericidal activity [5]. The aldoxime derivatives were a subject of our recent patent application [6] concerning antifungal activity against plant pathogens. There is a continuous need for new selective protection agents due to appearance of growing pathogens resistance. In continuation of our work on aryl aldehydes Schiff bases we undertook the synthesis of new oxime derivatives as potentially biologically active compounds. Herein, we present results of our research on preparation and biological screening of several aryl aldoxime ethers and esters against dermatophytes Trichophyton mentagrophytes (TM), Microsporum canis (MC); M. cookei, and M. gypseum (MG). T. mentagrophytes and M. canis are zoophilic fungal species infecting skin, hair and nails. M. cookei and M. gypseum are geophilic fungal species of a worldwide distribution, which cause skin infections in animals and humans, particularly children and rural workers during warm humid weather. Dermatophytoses are most often treated with the imidazole derivatives such as clotrimazole, ketoconazole, bifonazole, econazole, miconazole or triazole derivatives such as fluconazole, itraconazole, which interfere with fungal ergosterol synthesis by inhibiting lanosterol 14-demethylase [14,22]. These strong systemic antifungal drugs are usually effective to cure the disease, but they often have side effects, growing pathogen resistance is observed and more immunosuppressed patients are at risk for these infections. Other frequently applied drugs include griseofulvin (spirocyclohexenodione derivative), allylamine derivatives (terbinafine), [8], short and medium-chain fatty acids such as formic, propionic, lactic, tartaric and citric acids [19], thiazole derivatives [2], 1,3,4-thiadiazole derivatives [13], dihaloquinolinols [3,4] or simple sodium pyrithione (sodium 2pyridinethiol-1-oxide) [15]. The other agents are derivatives of natural quartenized polysaccharide chitosan [18], essential oils and various organic extracts [1,20].
Test organisms Fungi T. mentagrophytes ATCC 9533, M. gypseum ATCC 6231, M. cookei ATCC 13275 were obtained from American Type Culture Collection (ATCC collection). The test strains were maintained on Sabouraud’s Dextrose Agar (SDA) (Oxoid, UK) slants of pH 5.6, were stored in refrigerator at 4 8C and were transferred every 6—8 weeks to a fresh medium.
Fungicidal testing Determination of minimum inhibitory concentration (MIC) and minimum fungicide concentration (MFC) for dermatophytes The aim of this experiment was to determine the sensitivity of fungi to various concentrations of the test compounds and to determine the minimal concentrations (MIC) of the test compounds which completely inhibit the visible growth of fungi on the agar medium and to find the minimal fungicidal concentrations (MFC) values which kill 100% of a particular fungus. The test was performed on the Sabouraud Dextrose Agar (SDA) substrate in concentration range from 0.25% to 2%. Acetone solutions of test compounds were applied in an amount of 1 mL to the surface of agar-solidified medium on Petri dishes and then uniformly distributed and allowed to evaporate the solvent under aseptic conditions. Thereafter, the plates were loaded with mycelial discs (5 mm diameter) cut from homogeneous 5—7-day-old cultures of fungi grown on a SDA medium. As a control acetone was applied to the agar medium followed by mycelia discs after evaporation of acetone. The test was performed in three replications. As a reference, clotrimazole was used. As the value of minimum inhibitory concentration (MIC) the concentration of a compound limiting the fungus colony growth to 7 mm, i.e. 2 mm beyond the diameter of the incorporated inoculum, was adopted. Fungal inocula considered as negative (no growth) in the MIC test were incorporated into solid medium (SDA) without the addition of the test compounds and were incubated at the optimum temperature and time for the growth of the test fungi. As the value of the minimum fungicidal concentration (MFC), the concentration of compound causing total lack of growth of a fungus (macroscopic evaluation) was adopted.
Synthesis of tested compounds Reagent grade chemicals were used without further purification unless otherwise noted. Spectra were obtained as follows: IR spectra on a JASCO FTIR-420 spectrometer, 1H NMR
Please cite this article in press as: Marek W, et al. Synthesis and fungistatic activity of aryl aldoxime derivatives. Journal De Mycologie Médicale (2014), http://dx.doi.org/10.1016/j.mycmed.2014.10.026
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Synthesis and fungistatic activity of aryl aldoxime derivatives spectra on a Varian 200 UNITY plus 200, spectrometer in deuterated chloroform. Chemical shifts are given in ppm (d) relative to TMS as an internal standard, coupling constants are reported in Hz. EI mass spectra were run on a AMD M-40, HR EI mass spectra on a AMD 604. The octanol/water partition coefficients (clogP) were calculated using the computer program Hyperchem 7.5.
Typical procedure for synthesis of oxime ethers 3a, 4a A solution of oxime 2a (0.86 g, 4.75 mmol), DMSO (7 mL), pentyl bromide (4.3 g, 28.5 mmol), and potassium hydroxide (2.8 g) in ethanol (9 mL) was stirred at room temperature for half an hour. Then, brine was added (15 mL) and the mixture was extracted with ethyl acetate. The organic layer was washed with brine. After drying over anhydrous MgSO4, the solvent was evaporated under vacuum. The product was obtained as a yellow oil 0.55 g (46%). IR (neat) 2932, 1607, 1511, 998, 834 cm1; 1H NMR (CDCl3, 200 MHz) d 8.03 (s, 1H, HC = N), 7.51 (d, J = 9.0 Hz, 2H, H-2,6), 7.03 (d, J = 9.0 Hz, 2H, H-3,5), 5.19 (s, 2H, O-CH2-O), 4.14 (t, J = 6.6 Hz, 2H, O-CH2-CH2), 3.48 (s, 3H, OCH3), 0.92 (m, 3H, CH3). EI MS m/z (%of intensity) 251 (60), 250 (23), 220 (60), 192 (46). HR EI MS calcd. for C14H21NO3: 251.1521, found: 251.1527.
Typical procedure for synthesis of oxime ethers 5a—f A mixture of oxime 2a (0.4 g, 2 mmol), DMSO (3 mL), ethyl bromoacetate (0.5 mL, 4.95 mmol) and potassium carbonate
3 (3 g) in water (2 mL) was stirred at room temperature for 18 h. Then, 20 mL of brine was added and the solution was extracted with ethyl acetate. After drying over anhydrous MgSO4, the solvent was evaporated under vacuum. The product was obtained as a yellow oil 0.3 g (75%). IR (KBr) 2932, 1754, 1606, 1510, 1152, 999, 836, 532 cm1. 1H NMR (CDCl3, 200 MHz) d 8.16 (s, 1H, HC = N), 7.52 (d, J = 8.8 Hz, 2H, H-2, 6), 7.02 (d, J = 8.8 Hz, 2H, H-3, 5), 5.20 (s, 2H, OCH2O), 4.69 (s, 2H, OCH2C = O), 4.25 (q, J = 7.2 Hz, 2H, OCH2CH3), 3.48 (s, 3H, OCH3), 1.29 (t, J = 7.2 Hz, 3H, CH3). EI MS m/z (%) 267 (75), 137 (20), 164 (21), 134 (20). HR EIMS calc. for C13H17NO5: 267.11067; found: 267.11076.
Typical procedure for synthesis of oxime esters 6e and f A solution of the oxime 2e (0.78 g, 4.1 mmol) and triethylamine (0.41 g, 4.1 mmol) in methylene chloride (20 mL) was stirred at 0 8C for 5 minutes. Then, a solution of crotonoyl chloride (0.82 mL, 4.1 mmol) was added and the solution was stirred for 20 hours. After this time, the reaction mixture was washed successively with 10% cold acetic acid (5 mL), 10% sodium carbonate (5 mL), brine and water. Product was obtained as a white solid 0.72 g (68%). IR (KBr) 1753, 1654, 1584, 1475, 1387, 1296, 1141, 1091, 986, 826 cm1; 1 H NMR (CDCl3, 200 MHz) d 8.78 (s, 1H, HC = N), 7.62 (d, J = 8.4 Hz, 1H, H-60 ), 7.55 (d, J = 1.8 Hz, 1H, H-30 ), 7.42 (qd, J = 15.8; 1.9 Hz, 1 H, H-3), 7.38 (dd, J = 8.4; 1.9 Hz, 1H, H50 ), 5.97 (dd, J = 15.8; 1.9 Hz; 1H, -CH = CH-), 1.97 (dd, J = 7.0; 1.9 Hz, 3H). EI MS m/z (%) 173 (17), 171 (23), 147 (20), 136 (31). HR EI MS, calc. for C11H9Cl2NO2: 257.0010; found: 257.0018.
Scheme 1 Synthesis of oxime ethers and esters 3—6. i: NH2OH HCl, NaOH, rt, 10 h; ii: AlkBr, KOH, DMSO-H2O, rt, 0.5 h; iii: BrCO2Et, K2CO3, DMSO, rt, 18 h; iv: MeCH = CHCOCl, NEt3, CH2Cl2, 0 8C > rt, 20 h. ´ rature ambiante, 10 h ; ii : AlkBr, KOH, DMSO-H2O, ` se des ´ethers et des esters 3—6 d’oxime. i : NH2OH HCl, NaOH, tempe Synthe ´ rature ambiante, 18 h ; iv : MeCH = CHCOCl, NEt3, CH2Cl2, ´ rature ambiante, 0,5 h ; iii : BrCO2Et, K2CO3, DMSO, tempe tempe 0 8C > rt, 20 h. Please cite this article in press as: Marek W, et al. Synthesis and fungistatic activity of aryl aldoxime derivatives. Journal De Mycologie Médicale (2014), http://dx.doi.org/10.1016/j.mycmed.2014.10.026
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Table 1 Antifungal activity of oxime ethers and esters against dermatophytes. ´ antifongique des ´ethers et des esters d’oxime contre les dermatophytes. Activite Number
Compound/clog
5e
N O CH2 -COOEt
Microsporum canis
Microsporum gypseum
Microsporum cookei
Trichophyton mentagrophytes
MIC (%)
MFC (%)
MIC (%)
MFC (%)
MIC (%)
MFC (%)
MIC (%)
MFC (%)
1
1.5
1
1
1.5
1.5
1
1.5
2
>2
1.5
1.5
2
2
0.5
1.5
>2
>2
1
1.5
1.5
1.5
1.5
1.5
1.5
2
1
1.5
1
1.5
1
>2
2
>2
1.5
1.5
1.5
1.5
1.5
2
1.5
2
1.5
1.5
1
1
1.5
2
2
>2
2
2
>2
>2
>2
>2
>2
>2
2
2
>2
>2
>2
>2
>2
>2
2
2
>2
>2
2
>2
2
>2
1.5
1.5
1.5
>2
1.5
2
Cl
4.46 Cl
5f
N O CH2-COOEt
3.98 CF 3
5c
N O CH2-COOEt OMOM
3.02
Cl
5d
N O CH2-COOEt
4.35
5a
N O CH2-COOEt
2.53 OMOM
5b
N O CH2-COOEt OMOM
2.13
3c
N O C 2H5 OMOM
2.92
Cl
4c
N O C 5H11 OMOM
4.51
Cl
4e
N
O
C5H 11
Cl
5.96 Cl
3a
N O
C2 H5
2.43 OMOM
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Table 1 (Continued )
Number
Compound/clog
4a
N O
C5H11
Microsporum canis
Microsporum gypseum
Microsporum cookei
Trichophyton mentagrophytes
MIC (%)
MFC (%)
MIC (%)
MFC (%)
MIC (%)
MFC (%)
MIC (%)
MFC (%)
>2
>2
1.5
2
2
2
>2
>2
1.5
2
0.25
1
1
1
1.5
2
2
>2
1
1.5
0.5
1
1
2
2
2
< 0.25
0.25
< 0.25
< 0.25
< 0.25
< 0.25
4.03 OMOM
6f
N O COCH=CHCH3
4.09 CF3
6e
N O COCH=CHCH 3 Cl
5.02 Cl
Clotrimazole a
Minimal inhibitory concentration (MIC) is the lowest concentration of an antimicrobial that will totally inhibit the visible growth of a microorganism. Minimal fungicidal concentration (MFC) is the lowest concentration of an antifungal agent required to kill 100% of a particular fungus. a Reference compound.
Results and discussion Synthesis of the title compounds is outlined on Scheme 1. In the hydroxysubstituted starting benzaldehydes the OH group was protected as a methoxymethyl (MOM) ether using P2O5 catalyzed acetal exchange reaction with dimethoxymethane in chloroform in the presence of diisopropylethylamine [7] rather than an older procedure with carcinogenic chloromethyl methyl ether. Some pyrrole derivatives with 1-MOM substituents showed biological activity [9]. The aldehydes 1a—1f were then converted to the oximes with hydroxylamine hydrochloride and aqueous sodium hydroxide. E configuration of the oximes was determined on the basis of chemical shift values of HC = N proton in 1H NMR spectra above 8.0 ppm [12,16,21]. We have performed arylaldehyde oxime alkylation with simple alkyl bromides in the presence of aqueous-DMSO solutions of potassium hydroxide following the published procedure [11]. On the other hand, oxime alkylation with ethyl bromoacetate was carried out in aqueous-DMSO solutions of potassium carbonate. Exemplary deprotection of the MOM group was smoothly performed for ether 3a with a methanolic solution of hydrochloric acid by modification of the published procedure [24]. Oximes were acylated with an acyl chloride in dichloromethane in the presence of triethylamine as a base.
Biological activity and structure activity relationship The obtained oxime derivatives were evaluated in vitro against dermatophytes T. mentagrophytes (TM), M. canis
(MC); M. cookei, and M. gypseum. The results shown in Table 1 indicate diverse antifungal activity. In comparison to the reference compound, clotrimazole, the acetates 5e, 5d, and 5b as well as the crotonate 6f were more effective against M. canis. However, against the other examined pathogens clotrimazole showed at least for times higher activity than the described oxime derivatives. The synthesized oxime derivatives can be classified into three groups differing in phenyl ring and oxime part substituents. Compounds from the first group are benzaldoxime acetates 5a—f. Four ethers from this group 5b, 5d—f showed moderate activity against T. mentagrophytes (TM), M. cookei, and/or M. gypseum fungal strains (Table 1). The second group includes five simple benzaldoxime alkyl ethers 3a, 3c, 4a, 4c, 4e. One of them, ether 3a displayed a moderate inhibitory activity against T. mentagrophytes (TM) and M. gypseum fungal strains. Compounds from the third group are most active benzaldoxime esters 6f and 6e showing relatively good potency against respectively, M. cookei, and M. gypseum fungal strains. Analyzing structure activity relationship for the obtained esters generally derivatives with electron-withdrawing groups (EWG) showed higher fungicidal activity than esters with electron-donating groups (EDG) (compare 5e and 5f to 5a and 5d). In the first group, the activity was higher for 5e than for 5f with a weaker EWG character. Comparison of the moderate displayed fungicidal activity with the other groups of compounds showed that oxime derivatives were more potent than organic acids (MIC of ca. 5% or 50,000 mg/mL) [19]. However, the other classes of antifungal compounds in clinical use exhibit higher activities. Terpenoid quinines show MIC against T. mentagrophytes
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of 2—50 mg/mL [8], azoles show MIC in the range 1—64 mg/ mL [14,17], triazoles display MIC of ca. 8 mg/mL and quartenized chitosan derivatives exhibit MIC in the range 125— 1000 mg/mL [18]. Mechanism of fungicidal activity was well established for azole fungicides. For this group of compounds it involves interaction with membrane-bound enzyme, fungal lanosterol 14a-demethylase [17], which is part of the ergosterol biosynthetic pathway. The resulting ergosterol decrease renders fungal cells vulnerable to further membrane damage. Similarly in case of a quite different group of potential fungistatic agents, organic acids, the main targets are cell walls and membrane proteins [19]. Mechanism of quaternized chitosan derivatives against fungi remains debatable, but generally, it is attributed to a formation of polyelectrolyte complex between positively charged quaternary ammonium salts and negatively charged cell walls of fungi leading to cell wall disruption [18]. In light of the above data it can be tentatively assumed that described here oxime derivatives interact also with fungal wall enzymes. The antifungal activity can be correlated with lipophilicity of the oxime derivatives measured by the logarithm of octanol-water partition coefficient clogP [10]. Unfortunately no simple dependence was found between the calculated clogP values and the biological activity. However, the optimal ranges of clogP as a measure of lipophilicity of the synthesized benzaldoxime derivatives could be discerned. For the most active against M. canis oxime acetate derivative 5e, 5d clogP fell in the range of 4.0—4.5. In case of compounds most active against M. cookei the optimal ranges of lipophilicity corresponded to clogP of 2.0—2.5 (6f, 5b) and 4.0—4.5 for acetate with strongly electron-withdrawing substituents 5e. For compounds most potent against M. gypseum (6e, 6f, 5b, 5d) and T. mentagrophytes (5f, 5e) the advantageous ranges of lipophilicity were those with clogP values of 2.0—2.5 and 4.0—5.0.
Conclusions Several new aryl aldoxime ethers and esters have been prepared. The obtained compounds characterized by spectroscopic data (IR, 1H NMR and MS) showed a moderate antifungal activity particularly against dermatophytes T. mentagrophytes (TM), M. cookei. The observed biological potency showed some correlation with the lipophilicity of the compounds measured by octanol-water partition coefficient clogP. Based on the obtained results syntheses of new, more potent derivatives could be envisaged. Research is in progress to enhance the biological activity of the Schiff base type derivatives.
Disclosure of interest The authors declare that they have no conflicts of interest concerning this article.
Acknowledgements This work was supported in part by the Polish Ministry of Science and Higher Education (Grant 429/E-142/2013) which is gratefully acknowledged.
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