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Journal of the Chilean Chemical Society

On-line version ISSN 0717-9707

J. Chil. Chem. Soc. vol.61 no.3 Concepción Sept. 2016

http://dx.doi.org/10.4067/S0717-97072016000300015 

 

SYNTHESIS AND ANTIFUNGAL ACTIVITY OF DIARYL HYDRAZONES FROM 2,4-DINITROPHENYLHYDRAZINE

 

SERGIO ORTIZ,a RONALD NELSON,a VÍCTOR KESTERNICH,* MARCIA PÉREZ-FEHRMANN,a* PHILIPPE CHRISTENb AND LAURENCE MARCOURT.b

a Departamento de Química, Universidad Católica del Norte, Av. Angamos 0610, Antofagasta, Chile.
b
School of Pharmaceutical Sciences, University of Geneva, University of Lausanne, Quai Ernest-Ansermet 30, CH-1211, Geneva 4, Switzerland.
* e-mail: maperez@ucn.cl


ABSTRACT

A new series of diarylhydrazones derived from 2,4-dinitrophenylhydrazine were synthesized via condensation with aromatic aldehydes whose structures have been determined by mass spectrometry, infrared spectroscopy, and nuclear magnetic resonance spectra. Yields were 50-99%. All compounds were screened in vitro for their antifungal activity. Preliminary results indicated that compounds 3g and 3h exhibited promising antifungal potency. Understanding of the structure of these compounds establishes a preliminary structure-activity relationship to form the basis of further investigation.

Keywords: Antifungal Activity, Diarylhydrazones, Schiff bases.


 

INTRODUCTION

Aryl hydrazones are key compounds for the synthesis of heterocyclic rings such as indoles and pyrazoles.1-3 In recent decades the use and interest in Schiff bases has increased because of their wide range of applications, including biological, organic, inorganic and analytical chemical uses. They are used as pigments, dyes, catalysts, ligands in organometallic complexes and polymer stabilisers.4-9 The biological activity of these compounds results in a wide variety of effects, including antidepressant, analgesic, anti-inflammatory, antiplatelet, antimalarial, antimicrobial, antimycobacterial, antitumor and antioxidant.9-11 However, the antifungal activity of hydrazones is known only from reports on acylhydrazones.12-14

RESULT AND DISCUSSION

A new series of diarylhydrazones 3a-l was obtained from 2,4-dinitrophenylhydrazine 1 and aromatic aldehydes 2a-l (Scheme 1). The new series was synthesized through formation of a hemiaminal, between an amine and the corresponding aldehyde, with subsequent dehydration. The acidic medium was provided by the addition of sulfuric acid to facilitate the dehydration process, and ethanol was used as the solvent.

 

Scheme 1. Synthesis of diarylhydrazones 3a-l.

 

The spectroscopic data (1H NMR, 13C NMR and IR) were consistent with the proposed structures for compounds 3a-l (Table 1). The hydrazone bond was characterised by the presence of a band at 1614-1621 cm-1 corresponding to C=N stretching and a band at 3270-3290 cm-1 corresponding to N–H stretching in FT-IR and two singlets at δH 8.61-9.10 ppm (N=C–H) and 11.57-11.96 ppm (N–H) in the 1H NMR spectrum. In the 13C NMR spectra, a chemical shift was seen at 5c 138.9-150.7 ppm corresponding to the imine bond (C=N).

 

Table 1. Spectroscopy of newly synthesised compounds 3a-l.

 

All compounds were tested in vitro for antifungal activity at a concentration of 400 μg/mL in 2% DMSO in Sabouraud-dextrose broth by counting colony-forming units. Standardised strains of C. dubliniensis CBS 7987, C. glabrata ATCC 2001, C. tropicalis ATCC 13803 and C. krusei ATCC 6258 and fluconazole, as the reference drug, were used to test the antifungal activity of the compounds. Preliminary in vitro screening of newly synthesised compounds (Table 2) showed compounds 3g and 3h were active against three of the Candida strains: C. krusei, C. tropicalis and C. glabrata. The compounds showed no antifungal activity against C. dubliniensis.

 

Table 2: Percent inhibition of Candida species by newly
synthesised compounds

a concentration 400 μg/mL
b solvent control
c reference drug, fluconazole

 

In a second study, the active compounds were tested on Candida strains at decreased concentrations: 200 μg/mL and 100 μg/mL (Table 3). Compound 3g was the most active compound, showing up to 41% of inhibition of C. tropicalis at a concentration of 100 μg/mL. Compound 3h showed a decrease in activity with decreasing concentration.

 

Table 3. Percent inhibition of Candida species at different
concentrations by compounds 3g, 3h and fluconazole (Flu).

 

In general, all compounds nonhalogenated not exhibit antifungal activity. This could be due to the lipophilicity of the compounds since halogens improve this property.15 Both active compounds (3g and 3h) have chlorine atoms in the aromatic ring. Compound 3h has two chlorine atoms in the ortho position of the ring, while compound 3g has a para monosubstitution of chlorine. Compound 3g showed greater inhibition of three Candida strains than compound 3h. This may be due to the existence of a chlorine atom in the ortho position in compound 3h. Notably, compound 3f presents monosubstitution in the ortho position by a chlorine atom, but no antifungal properties. We infer that a substitution of chlorine in the para position is favorable for antifungal activity. However, the presence of a second atom of chlorine apparently decreases the activity of the compound; likewise the absence of chlorine generates a completely inactive compound. Other halogens in the para position were tested, but do not show antifungal activity. Other authors have reported a high resistance of Candida spp. to nitro hydrazine derivatives.16 C. dubliniensis is known for its resistance to azoles, and in this case we observed that compounds are inactive against this strain.17

EXPERIMENTAL

The reagents and solvents used in this work were obtained from Fluka, Aldrich or Merck and were used without further purification. Melting points were determined on a Kofler-type apparatus and are uncorrected. The infrared spectroscopy (IR) was done on a Perkin-Elmer 200 spectrophotometer with KBr. Nuclear magnetic resonance (NMR) spectra were collected in DMSO-d6 or CDCl3 on a Varian Unity Inova 500 MHz spectrometer equipped with a microflow probe from Protasis. Mass spectra (MS) were recorded on a Micromass-LCT Premier Time-of-Flight electrospray (ESI) spectrometer with Acquity UPLC (Ultra Performance Liquid Chromatography) interface system. Thin-layer chromatography (TLC) was performed on silica gel plates Merck 60 F254 and components were visualised by spraying with phosphomolybdic acid reagent, followed by heating.

General synthesis procedure

To a solution of 2,4-dinitrophenylhydrazine 1 (300.0 mg, 1.51 mmol) and the corresponding aldehyde 2a-l (1.51 mmol) in 50.0 mL of ethanol was added 0.5 mL of concentrated sulfuric acid. The mixture was stirred for one hour at room temperature, then cooled in an ice bath and the precipitate was collected by filtration. The precipitate was dried for four hours at 60°C and crystallized from acetone, ethanol or isopropanol at room temperature.

(E)-1-benzylidene-2-(2,4-dinitrophenyl)hydrazine (3a)

Compound 3a was obtained as orange crystals (acetone) at 74% yield, mp: 207-208°C, Rf: 0.62 (hexane:EtOAc, 7:3). IR (cm-1) ν: 3286 (N–H), 3104 (Csp2—H), 1620 (N=C), 1588 (CAr—CAr), 1509 (NO2). 1H-NMR (DMSO-d6, 500 MHz) δ (ppm): 7.50 (m, 3H), 7.82 (dd, J = 2.0, 7.6 Hz, 2H), 8.13 (d, J = 9.6 Hz, 1H), 8.39 (dd, J = 2.7, 9.6 Hz, 1H), 8.72 (s, 1H, N=CH), 8.88 (d, J = 2.7 Hz, 1H), 11.68 (s, 1H, N—H). 13C-NMR (DMSO-d6, 125 MHz) δ (ppm): 116.8 (CH), 123.0 (CH), 127.4 (CH), 128.9 (CH), 129.5 (C), 129.9 (CH), 130.5 (CH), 133.8 (C), 137.0 (C), 144.6 (C), 149.4 (CH, N=C). HRESIMS(+): calculated for C13H11N4O4 [M+H]+: 287.07802; found 287.08102. (

E)-2-((2-(2,4-dinitrophenyl)hydrazono)methyl)phenol (3b)

Compound 3b was obtained as orange crystals (EtOH) at 99% yield, mp: 260—261°C, Rf 0.55 (hexane:EtOAc, 7:3). IR (cm-1) ν: 3365 (O–H), 3273 (N—H), 3099 (Csp2—H), 1620 (N=C), 1591 (CAr—CAr), 1510 (NO2). 1H-NMR (DMSO-d6, 500 MHz) δ (ppm): 6.92 (dd, J = 1.1, 8.3 Hz, 2H), 7.30 (t, J = 7.2 Hz, 1H), 7.85 (d, J= 7.7 Hz, 1H), 8.04 (d, J = 9.6 Hz, 1H), 8.37 (d, J = 9.7 Hz, 1H), 8.87 (d, J = 2.4 Hz, 1H), 8.96 (s, 1H, N=CH), 10.22 (s, 1H, OH), 11.72 (s, 1H, N–H). 13C-NMR (DMSO-d6, 125 MHz) δ (ppm): 116.3 (CH), 116.6 (CH), 119.5 (CH), 120.1 (C), 123.1 (CH), 126.6 (CH), 129.5 (C), 129.7 (CH), 131.9 (CH), 137.0 (C), 144.6 (C), 146.7 (CH, N=C), 156.9 (C). HRESIMS(+): calculated for C13H11N4O5 [M+H]+: 303.07293; found 303.07416.

(E)-1-(2,4-dinitrophenyl)-2-(2-methoxybenzylidene)hydrazine (3c)

Compound 3c was obtained as red crystals (acetone) at 97% yield, mp: 196—197°C, Rf: 0.60 (hexane:EtOAc, 7:3). IR (cm-1) ν: 3270 (N—H), 3110 (Csp2—H), 2935 (Csp3—H), 1616 (N=C), 1585 (CAr-CAr), 1502 (NO2), 1255 (C-O). 1H-NmR (DMSO-d6, 500 MHz) δ (ppm): 4.02 (s, 3H, OCH3), 7.05 (t, J = 7.5 Hz, 1H), 7.14 (d, J = 7.6 Hz, 1H,), 7.46 (t, J = 7.7 Hz, 1H,), 7.97 (d, J = 7.2, 1H), 8.10 (d, J = 9.6 Hz, 1H), 8.36 (d, J = 10.0 Hz, 1H), 8.86 (s, 1H), 8.99 (s, 1H, N=CH), 11.76 (s, 1H, N–H). 13C-NMR (DMSO-d6, 125 MHz) δ (ppm): 56.5 (CH3), 112.1 (CH), 116.8 (CH), 120.8 (CH), 122.0 (C), 123.0 (CH), 125.8 (CH), 129.4 (C), 129.6 (CH), 132.1 (CH), 136.8 (C), 144.5 (C), 144.9 (CH, N=C), 158.0 (C). HRESIMS(+): calculated for C14H13N4O5 [M+H]+: 317.08858; found 317.09125.

(E)-4-((2-(2,4-dinitrophenyl)hydrazono)methyl)-2-methoxyphenol (3d)

Compound 3d was obtained as red crystals (EtOH) at 92% yield, mp: 272—273°C, Rf: 0.30 (hexane:EtOAc, 7:3). IR (cm-1) ν: 3385(O—H), 3278 (N—H), 3108 (Csp2—H), 2942 (Csp3—H), 1621 (N=C), 1589 (CAr—CAr), 1515 (NO2), 1269 (C-O). 1H-NMR (DMSO-d6, 500 MHz) δ (ppm): 3.87 (s, 3H, OCH3), 6.88 (d, J = 8.1 Hz, 1H), 7.18 (dd, J = 1.9, 8.2 Hz, 1H), 7.40 (d, J = 1.9 Hz, 1H), 8.09 (d, J = 9.66 Hz, 1H), 8.34 (dd, J = 2.7, 9.6 Hz, 1H), 8.57 (s, 1H, N=CH), 8.87 (d, J = 2.6 Hz, 1H), 9.68 (s, 1H, OH), 11.59 (s, 1H, N–H). 13C-NMR (DMSO-d6, 125 MHz) δ (ppm): 56.2 (CH3), 110.2 (CH), 116.1 (CH), 117.2 (CH), 123.0 (CH), 123.6 (CH), 129.6 (C), 125.6 (C), 130.0 (CH), 136.7 (C), 145.0 (C), 148.6 (C), 149.9 (C), 150.7 (CH, N=C). HRESIMS(+): calculated for C14H13N4O6 [M+H]+: 333.08350; found 333.08572.

(E)-1-(2,4-dinitrophenyl)-2-(4-methoxybenzylidene)hydrazine (3e)

Compound 3e was obtained as red crystals (acetone) at 84% yield, mp: 253-254°C, Rf 0.54 (hexane:EtOAc, 7:3). IR (cm-1) ν: 3290 (N–H), 3112 (Csp2–H), 2944 (Csp3–H), 1621 (N=C), 1585 (CAr–CAr), 1515 (NO2), 1255 (C–O) 1H-NMR (DMSO-d6, 500 MHz) δ (ppm): 3.83 (s, 3H, OCH3), 7.06 (d, J = 8.30 Hz, 2H), 7.76 (d, J = 8.28 Hz, 2H), 8.09 (d, J = 9.60 Hz, 1H), 8.37 (dd, J = 2.72, 9.70 Hz, 1H), 8.65 (s, 1H, N=CH), 8.88 (d, J = 2.63 Hz, 1H), 11.60 (s, 1H, N–H). 13C-NMR (DMSO-d6, 125 MHz) δ (ppm): 55.4 (CH3), 114.5 (CH), 116.7 (CH), 123.0 (CH), 126.3 (C), 128.7 (C), 129.1 (CH), 129.7 (CH), 136.7 (C), 144.5 (C), 149.5 (CH, N=C), 161.3 (C). HRESIMS(+): calculated for C14H3N4O5 [M+H]+: 317.08858; found 317.09015.

(E)-1-(2-chlorobenzylidene)-2-(2,4-dinitrophenyl)hydrazine (3f)

Compound 3f was obtained as orange crystals (EtOH) at 89% yield, mp: 216–217°C, Rf 0.60 (hexane:EtOAc, 7:3). IR (cm-1) ν: 3288 (N–H), 3104 (Csp2–H), 1616 (N=C), 1582 (CAr–CAr), 1508 (NO2). 1H -NMR (DMSO-d6, 500 MHz) δ (ppm): 7.46 (td, J = 1.4, 7.4 Hz, 1H), 7.49 (td, J = 2.3, 7.4 Hz, 1H), 7.56 (dd, J = 1.6, 7.8 Hz, 1H), 8.14 (dd J = 1.7, 9.5 Hz, 1H), 8.39 (dd, J = 2.7, 9.6 Hz, 1H), 8.87 (d, J = 2.7 Hz, 1H), 9.11 (s, 1H, N=CH), 11.95 (s, 1H, N–H). 13C-NMR (DMSO-d6, 125 MHz) δ (ppm): 116.7 (CH), 122.6 (CH), 127.0 (CH), 127.4 (CH), 129.4 CH), 129.5 (C), 129.8 (CH), 131.2 (C), 131.5 (CH), 133.4 (C), 137.2 (C), 144.2 (C), 144.8 (CH, N=C). HRESIMS(+): calculated for C13H10ClN4O4 [M+H]+: 321.03904; found 321.03925.

(E)-1-(4-chlorobenzylidene)-2-(2,4-dinitrophenyl)hydrazine (3g)

Compound 3g was obtained as orange crystals (iPrOH) at 90% yield, mp: 272–273°C, Rf: 0.63 (hexane:EtOAc, 7:3). IR (cm-1) ν: 3284 (N–H), 3090 (Csp2–H), 1615 (N=C), 1586 (CAr–CAr), 1511 (NO2). 1H-NMR (DMSO-d6, 500 MHz) δ (ppm): 7.57 (d, J = 8.5 Hz, 2H), 7.84 (d, J = 8.6 Hz, 2H), 8.11 (d, J = 9.6 Hz, 1H), 8.37 (d, J = 9.7 Hz, 1H), 8.70 (s, 1H, N=CH), 8.87 (d, J = 2.7 Hz, 1H,), 11.71 (s, 1H, N–H). 13C-NMR (DMSO-d6, 125 MHz) δ (ppm): 117.2 (CH), 123.5 (CH), 129.4 (CH), 129.5 (CH), 130.0 (CH), 130.4 (C), 133.3 (C), 135.4 (C), 137.4 (C), 144.4 (C), 148.5 (CH, N=C). HRESIMS(-): calculated for C13H8ClN4O4 [M–H]-: 3191.02339; found 319.02060.

(E)-1-(2,4-dichlorobenzylidene)-2-(2,4-dinitrophenyl)hydrazine (3h)

Compound 3h was obtained as yellow crystals (EtOH) at 89% yield, mp: 222-223°C, Rf: 0.70 (hexanes:EtOAc, 7:3). IR (cm-1) ν: 3286 (N–H), 3096 (Csp2–H), 1614 (N=C), 1589 (CAr–CAr), 1512 (NO2). 1H-NMR (DMSO-d6, 500 MHz) δ (ppm): 7.55 (dd, J = 1.6,'8.4 Hz, 1H), 7.75 (d, J = 2.1 Hz, 1H), 8.14 (d, J = 9.5 Hz, 1H), 8.15 (d, J = 8.7 Hz, 1H), 8.38 (dd, J = 2.7, 9.7 Hz, 1H), 8.87 (d, J = 2.7 Hz, 1H), 9.07 (s, 1H, N=CH), 11.97 (s, 1H, N–H). 13C-NMR (DMSO-d6, 125 MHz) δ (ppm): 116.8 (CH), 122.6 (CH), 127.7 (CH), 128.2 (CH), 129.3 (CH), 129.3 (CH), 129.9 (C), 130.2 (C), 133.8 (C), 134.9 (C), 137.2 (C), 143.7 (CH, N=C), 144.1 (C). HRESIMS(+): calculated for C13H9Cl2N4O4 [M+H]+: 355.00007; found 355.00113.

(E)-1-(4-bromobenzylidene)-2-(2,4-dinitrophenyl)hydrazine (3i)

Compound 3i was obtained as orange crystals (iPrOH) at 95% yield, mp: 263–264°C, Rf: 0.70 (hexanes:EtOAc, 7:3). IR (cm-1) ν: 3297 (N–H), 3090 (Csp–H), 1619 (N=C), 1587 (CAr–CAr), 1510 (NO2). 1H-NMR (DMSO-d6, 500 MHz) δ (ppm): 7.69 (d, J = 8.4 Hz, 2H), 7.76 (d, J = 7.8 Hz, 2H), 8.05 (d, J = 8.9 Hz, 1H), 8.27 (s, 1H), 8.64 (s, 1H, N=CH), 8.82 (s, 1H), 11.73 (s, 1H, N–H). 13C-NMR (DMSO-d6, 125 MHz) δ (ppm): 116.5 (CH, d, J = 20.0 Hz), 117.2 (CH), 123.5 (CH), 130.1 (CH), 130.0 (CH, d, J = 8.6 Hz), 130.1 (C), 131.0 (C), 137.4 (C), 145.0 (C), 148.8 (CH, N=C), 163.5 (C-F, d, J = 251.8 Hz). HRESIMS(-): calculated for C13H8BrN4O4 [M–H]-: 362.97288; found 362.97180.

(E)-1-(2,4-dinitrophenyl)-2-(4-fluorobenzylidene)hydrazine (3j)

Compound 3j was obtained as orange crystals (iPrOH) at 83% yield, mp: 280-281°C, Rf: 0.61 (hexanes:EtOAc, 7:3). IR (cm-1) ν: 3286 (N–H), 3091 (Csp2–H), 1614 (N=C), 1589 (CAr–CAr), 1504 (NO2). 1H-NMR (DMSO-d6, 500 MHz) δ (ppm): 7.35 (t, J = 8.8 2H), 7.88 (dd, J = 5.7, 8.6 Hz, 2H), 8.11 (d, J = 9.6 Hz, 1H), 8.37 (dd, J = 2.7, 9.7 Hz, 1H), 8.71 (s, 1H, N=CH), 8.88 (d, J = 2.7 Hz, 1H), 11.67 (s, 1H, N–H). 13C-NMR (DMSO-d6, 125 MHz) δ (ppm): 116.5 (CH, d, J = 20.0 Hz), 117.2 (CH), 123.5 (CH), 130.1 (CH), 130.0 (CH, d, J = 8.6 Hz), 130.1 (C), 131.0 (C), 137.4 (C), 145.0 (C), 148.8 (CH, N=C), 163.5 (C-F, d, J = 251.8 Hz). HRESIMS(-): calculated for C13H8FN4O4 [M–H]-: 303.05294; found 303.05228.

(E)-1-(2,4-dinitrophenyl)-2-(4-nitrobenzylidene)hydrazine (3k)

Compound 3k was obtained as orange crystals (acetone) at 92% yield, mp: 349-350°C, Rf: 0.48 (hexanes:EtOAc, 7:3). IR (cm-1) ν: 3289 (N–H), 3091 (Csp2–H); 1616 (N=C), 1577 (CAr–CAr), 1508 (NO2). 1H-NMR (DMSO-d6, 500 MHz) δ (ppm): 8.07 (d, J = 8.53 Hz, 2h), 8.16 (d, J = 9.58 Hz, 1H), 8.34 (d, J = 8.59 Hz, 2H), 8.40 (d, J = 9.52 Hz, 1H), 8.81 (s, 1H, N=CH), 8.88 (d, J = 2.69 Hz, 1H), 11.85 (s, 1H, N–H). 13C-NMR (DMSO-d6, 125 MHz) δ (ppm): 117.0 (CH), 122.9 (CH), 124.2 (CH), 128.1 (CH), 129.6 (CH), 130.6 (C), 137.1 (C), 140.3 (C), 144.4 (C), 146.5 (CH, N=C), 147.9 (C). HRESIMS(-): calculated for C13H8N5O6 [M–H]-: 330.04744; found 330.04697.

(E)-1-(2,4-dinitrophenyl)-2-(furan-2-ylmethylene)hydrazine (3l)

Compound 3l was obtained as red precipitate at 50% yield, mp: 149–150°C, Rf: 0.52 (hexanes:EtOAc, 7:3). IR (cm-1) ν: 3280 (N–H), 3118 (Csp2–H), 1618 (N=C), 1581 (CAr–CAr), 1511 (NO2). 1H-NMR (DMSO-d6, 500 MHz) δ (ppm): 6.68 (dd, J = 1.8, 3.4 Hz, 1H), 6.99 (d, J = 3.4 Hz, 1H), 7.90, (d, J = 1.7 Hz, 1H), 7.95 (d, J = 9.6 Hz, 1H), 8.38 (dd, J = 2.7, 9.7 Hz, 1H), 8.62 (s, 1H, N=CH), 8.85 (d, J = 2.7 Hz, 1H), 11.66 (s, 1H, N–H). 13C-NMR (DMSO-d6, 125 MHz) δ (ppm): 112.5 (CH), 114.9 (CH), 116.6 (CH), 122.9 (CH), 129.4 (C), 129.8 (CH), 137.0 (C), 138.9 (CH, N=C), 144.3 (C), 145.8 (CH), 149.0 (C). HRESIMS(-): calculated for C11H7N4O5 [M–H]-: 275.04163; found 275.03949.

Antifungal test

The compounds were tested for their in vitro antifungal activity against Candida dubliniensis CBS 7987, C. glabrata ATCC 2001, C. tropicalis ATCC 13803 and C. krusei ATCC 6258 strains by counting colonies with serial dilutions in liquid broth, for determination of MIC90. Fluconazole was used as the reference drug. All compounds and the reference drug were dissolved in dimethylsulfoxide (DMSO) at a concentration of 1000 μg/mL with subsequent dilution in Sabouraud-dextrose broth (400 μg/mL) to obtain a 2% solution. An initial inoculum was created using 4.8 mL Sabouraud-dextrose broth plus 0.1 mL of solution of each compound (400 μg/mL) and 0.1 mL of yeast strain matched to a 0.5% McFarland turbidity standard. This initial inoculum was incubated at 36°C for 48 hours. After this time, 100 mL of each inoculum was placed on Petri dishes with Sabouraud-dextrose agar, seeded with a seed rake and incubated at 36°C for 48 hours. Finally, we counted the colonies formed to calculate percent inhibition of each strain by each compound against the reference drug, as shown in Formula 1. Each assay was performed in triplicate. The same methodology was used for the tests of compounds at 200 μg/mL and 100 μg/mL.

Formula 1 : Preliminary calculation of percent
inhibition

CONCLUSION

In this work, we report screening of a series of diarylhydrazones synthesised from commercially available substances using a simple method with yields of 50–99%. Two of the compounds showed promising antifungal activity, establishing the first foundations for understanding of the correlation between structure and antifungal activity in this family of compounds that constitutes the basis for further structural modifications.

We acknowledge the European ChemBioFight project (grant agreement 269301) for financial support.

 

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