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. 2020 Nov 23;11(12):2470–2475. doi: 10.1021/acsmedchemlett.0c00449

Novel 2-Aryloxazoline Compounds Exhibit an Inhibitory Effect on Candida spp., Including Antifungal-Resistant Isolates

Luis M Z Argomedo †, Vinicius M Barroso ‡, Cristiane S Barreiro †, Mariana P Darbem †, Kelly Ishida ‡,*, Hélio A Stefani †,*
PMCID: PMC7734819  PMID: 33335669

Abstract

graphic file with name ml0c00449_0005.jpg

Because of the increased resistance to currently available antifungals, fungal infections represent a significant challenge to human health. Herein, we report the synthesis of 2-aryloxazoline derivatives from the reaction between l-threonine and derivatives of salicylic or naphthoic acid. In total, 26 compounds were obtained and tested against species of Candida, Cryptococcus, and Aspergillus. We found that all of the compounds inhibited the growth of Candida species at low concentrations (<0.25 μg/mL) and exhibited reduced hemolytic and cytotoxic activities. Additionally, compounds 4i and 9i were especially effective against antifungal-resistant isolates and the emerging fungus Candida auris. However, the compounds were less active on Cryptococcus and Aspergillus. Because of the improved in vitro antifungal efficacy and attenuated cytotoxicity, these two 2-aryloxazolines obtained from salicylic and naphthoic acid derivatives, respectively, may be considered lead molecules for the development of novel antifungal drugs.

Keywords: Candida auris, Fluconazole, Resistance, 2-Aryloxazoline, l-threonine, α-aminoalcohols

In the past decades, invasive fungal infections (IFIs) have been increasing in number and severity. The main fungal genera associated with high mortality rates include Candida, Cryptococcus, and Aspergillus, accounting for ∼90% of all IFIs.1 Notably, while Candida albicans is the fungal species responsible most of the IFIs in the hospital setting, the incidence of IFIs caused by Candida non-albicans, especially species resistant to the antifungal agents, has increased.2,3

This scenario has increased the demand for new compounds against fungal infections; however, the development of antifungals has not kept up with this need.4 Previous studies demonstrated that several heterocyclic compounds possess antifungal properties.4,5 Indeed, oxazoline compounds have exhibited pharmacological activities,6 but few studies investigated their antifungal effects.7−11 In this regard, because of the medicinal importance of the oxazoline moiety, it represents a promising target for the development of new antifungals.

Different precursors and synthetic routes can yield oxazolinic compounds; however, they usually require high reaction times and numerous synthetic steps, consequently resulting in lower yields and chemical residues.12−14 The present study sought to synthesize new 2-aryloxazoline compounds, using a limited number of reaction steps. Additionally, we evaluated the cytotoxic effects and antifungal activity of these novel compounds on yeasts (Candida and Cryptococcus) and molds (Aspergillus).

The amino acid l-threonine represents a wider group of compounds, namely α-aminoalcohols.15,16 This α-aminoalcohol was used to obtain 2-aryloxazolines reacting with derivatives of salicylic and naphthoic acids.17,18 Following different synthetic routes (Schemes 1 and 2), two series (4 and 9) of 2-aryloxazolines derivatives with selective substitution were obtained. In total, our synthetic routes yielded 10 2-aryloxazolines from the reaction between l-threonine and salicylic acid derivatives and 16 2-aryloxazolines obtained from the reaction between l-threonine and naphthoic acid derivatives (Figures 1 and 2, respectively).

Scheme 1. Synthetic Route for 2-Aryloxazolines (4a–j) Obtained from Salicylic Acid Derivatives (1) and l-Threonine (2a).

Scheme 1

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Scheme 2. Synthesis of the 2-Aryloxazolines from Naphthoic Acid (5) and l-Threonine (2a–d) Derivatives.

Scheme 2

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(i) EDC·HCl, 1-HOBt, NMM, DCM, ultrasound, 6 h; (ii) SOCl2, CH2Cl2, rt, 24 h; (b) (i′) EDC·HCl, 1-HOBt, NMM, DCM, ultrasound, 1 h; (ii′) SOCl2, CH2Cl2, rt, 24 h; (iii′) LiOH (3.5 mmol, 3.5 equiv), THF-H2O (8:2, 10 mL), rt 2 h; (iv′) 9a SOCl2, MeOH, 0° C; (v′) 9b–9f, (R2 = furfuryl alcohol, allyl alcohol, MeOH, (R)-(−)-2,2-dimethyl-1,3-dioxolane-4-methanol), DMAP, EDC·HCl, THF, rt 16 h, 9f–9j (R1 = aminobenzothiazole, 1,2-diaminobenzene, ethylamine, 4-ethylaniline, propargylamine), EDC·HCl, 1-HOBt, NMM, CH2Cl2; (vi) 10, SOBr2, CH2Cl2 (5 mL), rt, 24 h; (vii) 11a–11c, Deoxo-Fluor, CH2Cl2, rt.

Figure 1.

Figure 1

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2-Aryloxazolines obtained from the reactions between l-threonine and salicylic acid derivatives and respective yields.

Figure 2.

Figure 2

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2-Aryloxazolines obtained from the reactions between l-threonine and naphthoic acid derivatives and respective yields.

As shown in Schemes 1 and 2, the synthesis of halogenated and nonhalogenated oxazoline compounds was initiated via an amidation step. Then the salicylic acid derivatives (1) or 1-hydroxy-2-naphthoic acid (5) were reacted with benzyl-protected l-threonine (2), which was obtained by refluxing l-threonine with benzyl alcohol.17,18

The amidation step was performed using 1.3 equiv of EDC (1-ethyl-3-(3-dimethylaminopropyl)carbodiimide), 1.2 equiv of 1-HOBt (1-hydroxybenzotriazole), and 1.5 equiv of NMM in dichloromethane as solvent, leading to the coupling products 3, 6, and 11, respectively (Schemes 1 and 2). We optimized this step of the reaction protocol by employing an ultrasonic bath,19 which significantly reduced the reaction time from 12 h, for the “on the bench” synthesis,20 to 1 h.

Regarding the oxazoline compounds derived from salicylic acid, 10 compounds were obtained with satisfactory yields ranging from 40–87% (4a–4j, Figure 1). As shown in Scheme 2, halogenation at position 4 of the naphthoic ring was achieved by using thionyl chloride (compound 7) or thionyl bromide (compound 10) as the cyclizing agent, while nonhalogenated products were obtained using Deoxofluor21 as the cyclizing agent (compounds 11a–11c). Additionally, the hydrolysis of and introduction of different amides and esters into compound 7 yielded compounds 9a–9j (Figure 2).

Here, we describe a straightforward synthetic route for obtaining 2-aryloxazoline compounds from only two or three reaction steps, which represents a substantial reduction when compared to the five steps required for the traditional synthetic route.17,18 The coupling reaction between l-threonine and the naphthoic or salicylic acid derivatives, followed by the simultaneous halogenation and cyclization, with inversion of configuration using excess SOCl2, provides a shorter, more efficient pathway for the synthesis of oxazolines.17,18

After obtaining 26 novel 2-aryloxazolines, we first performed the susceptibility testing against Candida species (i.e., C. albicans, Candida parapsilosis, Candida tropicalis, Candida glabrata, and Candida krusei), employing at least one isolate of each species that is both resistant and susceptible to fluconazole (FLC), frequently isolated from clinical samples. It is worth pointing out that Candida tropicalis ATCC 200956 is considered a multidrug-resistant strain (amphotericin B and triazoles such as FLC) (Table 1), corroborating with the previous data.22

Table 1. Antifungal Activity of 2-Aryloxazolines against Candida spp. and Cytotoxic Effect on Red Blood Cells (RBC) and Human Hepatic Cells (HepG2)a.

  Candida spp.
 RBC
 HepG2
compounds MIC geometric media MIC range HA50 SI CC50 SI
FLCb ND 1 to >128 >128 1 to >128 >128 1 to >128
AMB 0.08 ≤0.03–2 17 68 to >567 4 16 to >133
CAS 0.40 ≤0.03–2 >32 16 to >1067 32 16–1067
4a 0.87 ≤0.03–4 >128 32 to >4267 102 26 to >3400
4b 0.20 ≤0.03–1 >128 128 to >4267 100 100 to >3333
4c 0.25 0.06–1 >128 128 to >4267 62 62–1033
4d 0.27 ≤0.03–1 >128 128 to >4267 62 62 to >2067
4e 0.50 ≤0.03–4 >128 32 to >4267 100 25–3333
4f 0.33 ≤0.03–1 >128 128 to >4267 >128 128 to >4267
4g 0.19 ≤0.03–1 >128 128 to >4267 88 88 to >2933
4h 2.13 0.12–16 >128 8 to >1067 101 6–842
4i 0.14 ≤0.03–0.25 >128 512 to >4267 95 380 to >3167
4j 0.46 ≤0.03–1 >128 128 to >4267 64 64 to >2133
6 14.93 8 to >16 >128 >8 40 3–5
7 0.14 0.06–2 >128 64 to >2133 15 8–250
9a 0.70 0.25–8 >128 16 to >512 11 1–44
9b 0.23 ≤0.03–1 >128 128 to >4267 11 11 to >367
9c 0.12 ≤0.03 to >16 >128 8 to >4267 10 1 to >333
9d 0.40 ≤0.03–8 >128 16 to >4267 7.2 1 to >240
9e 0.25 ≤0.03–4 >128 32 to >4267 6 2 to >200
9f 0.33 0.06–1 >128 128 to >2133 >128 128 to >2133
9g 0.08 ≤0.03–0.25 >128 512 to >4267 33 132 to >1100
9h 0.04 ≤0.03–0.5 >128 256 to >4267 8.2 16 to >273
9i 0.06 ≤0.03–0.12 >128 1067 to >4267 16 133 to >533
9j 0.38 ≤0.03–4 >128 32 to >4267 90 23 to >3000
10 0.11 ≤0.03–0.5 >128 256 to >4267 9 18 to >300
11a 2.13 0.06–16 >128 8 to >2133 84 5–1400
11b 0.06 ≤0.03–1 >128 128 to >4267 >128 128 to >4267
11c 0.11 ≤0.03–0.5 >128 256 to >4267 88 176 to >2933
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a

The selectivity index (SI) for Candida spp. was determined for each compound. MIC, HA50, and CC50 values are in μg/mL. MIC, minimum inhibitory concentration; CC50, cytotoxic concentrations of 50% (a compound concentration yielding 50% cytotoxicity to HepG2); HA50, hemolytic activity of 50% (a compound concentration yielding 50% of hemolysis of RBC); AMB, amphotericin B; CAS, caspofungin; FLC, fluconazole; ND, not determined.

b

Fluconazole-resistant and fluconazole-susceptible isolates (see Supporting Information, Table S1).

The results demonstrated that salicylic acid-derived 2-aryloxazoline compounds (4a–4j, Figure 1) had minimum inhibitory concentration (MIC) values that were equal to or lower than FLC (Table 1 and Supporting Information, Table S1). From this series, compound 4i showed the highest inhibitory effect against Candida spp. (MICs ≤ 0.25 μg/mL), while 4h had the lowest (MICs: 0.12–16 μg/mL). Interestingly, compound 4a, the simplest salicylic acid-derived compound, had the highest yield (86%), presented MIC values that were similar to other analogues (MICs: ≤0.03–4 μg/mL) and was effective toward all Candida spp., including FLC-resistant strains (Table 1 and Supporting Information, Table S1). Upon closer examination of the chemical structures of the 2-aryloxazolines obtained from salicylic acid derivatives, it was apparent that the substituents influenced both the yield and antifungal effect. For example, compounds with azide and halogenated substituents at the C3 and C4 positions appear to be essential to the antifungal effect. This effect was particularly evident in compound 4i, which has chlorine at position C3 (Table 1, Figure 1).

Concerning the naphthoic acid-derived 2-aryloxazolines (14 compounds: 7, 9a–9j, 10, and 11a–11c, Figure 2), the yields for this group of compounds ranged from 55–89% and exhibited a greater antifungal effect when compared to the salicylic acid-derived compounds (Table 1). Moreover, these compounds showed a higher inhibitory effect on FLC-resistant Candida spp. strains (MICs: ≤0.03–0.5 μg/mL) when compared with FLC-susceptible strains (0.5–2 μg/mL). Notably, compounds 9g, 9h, and 9i were effective against both FLC-susceptible and FLC-resistant Candida spp. (MICs: ≤0.03–0.5 μg/mL) (Table 1 and Supporting Information, S1).

This particular type of oxazoline is characterized by having a substituent present on both lateral chains, thus placing the oxazoline ring at the center of the molecule. In our synthetic route, the naphthoic side chain was selectively nonsubstituted or substituted with halogens, and the carboxylate side chain was substituted with simple and electron-rich substituents (Figure 2). Overall, the yields were satisfactory, and unlike previous reports, the biological effect was augmented by the addition of an electron-rich substituent.23−25

Except for compound 11a, the nonhalogenated compounds (11b and 11c) exhibited antifungal activities similar to the halogenated compounds. When comparing compounds 7 and 11c, both compounds have electron-rich groups linked to the side chain carboxyl, but compound 7 has a chlorine present at the C4 position of the naphthoic ring. It is plausible that the electron-rich substituent is necessary for improving the inhibitory effect on fungal growth. It is also worth mentioning that we tested a dimer of the chlorinated oxazoline (compound 9j) and found that the antifungal activity was attenuated when compared to the monomer, compound 7 (Figure 2, Table 1).

The selectively chlorinated oxazolines (compounds 7, 9a–9j) had excellent antifungal effects and were slightly more effective against FLC-resistant Candida spp. isolates (Supporting Information, Table S1). Notably, compounds 9g, 9h, and 9i exhibited better inhibitory activity, as evidenced by MIC values less than 0.5 μg/mL (Table 1 and Supporting Information, Table S1). While compound 9g contains a propargyl substituent that provides relatively good electron density due to the triple bond, compounds 9h and 9i have additional aromatic rings and a heterocyclic ring, respectively (Figure 2). In this respect, compounds 9g and 9i exhibited the greatest inhibitory effect and presented the lowest MIC values against Candida spp. (≤0.03–0.25 μg/mL) (Table 1), thus representing promising lead molecules for the development of novel antifungal drugs.

We also tested the compound 6 to confirm that the oxazoline moiety is responsible for the observed biological activity. We found that this compound was ineffective against all of the yeast strains employed in the present study. Therefore, this result demonstrates that this moiety is essential for the observed antifungal action.

Additionally, the hemolytic and cytotoxic test results for all 2-aryloxazoline compounds are presented in Table 1. While none of the compounds were hemolytic, even at the highest concentration tested (128 μg/mL), some were cytotoxic to hepatic cells (HepG2 lineage). Furthermore, salicylic acid-derived compounds (CC50: 62 to >128 μg/mL) were less cytotoxic than naphthoic acid-derived compounds (CC50: 7.2 to >128 μg/mL). When we used these data to calculate the selectivity index (SI) for RBCs and HepG2 cells, the SI values for compounds 4b, 4f, 4i, 9f, 9g, 9i, and 11b and 11c were all greater than 60, which is considered safe.26 On the basis of these results, the salicylic acid-derived compound 4i and the naphthoic acid-derived compounds 9g and 9i should be considered promising lead molecules for the development of antifungals. These drug scaffolds could likely yield additional compounds that exhibit even lower MIC values and reduced in vitro cytotoxicity (i.e., higher SI values).

In addition to testing the susceptibility of the five main species of Candida that are frequently isolated from clinical material to these novel compounds, we also evaluated the efficacy of compounds 4i and 9i against emerging species from Candida hemeulonii complex, including multidrug-resistant species (Table 2). We found that both 4i and 9i were effective at inhibiting the growth of these yeast species at concentrations below 2 μg/mL (Table 2).

Table 2. Antifungal Activity of 2-Aryloxazolines 4i and 9i against Species from Candida haemulonii Complexa.

  MIC (μg/mL)
species 4i 9i FLC AMB CAS
C. auris CBS 10913 0.06 0.06 2 0.5 0.12
C. auris CBS 12766 2 2 >64R 2R 0.25
C. duobushemeulonii CBS 7799 0.5 0.06 >64R 4R 0.25
C. pseudohemeulonii CBS 10004 0.25 0.03 16R 8R 0.5
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a

MIC, minimum inhibitory concentration; FLC, fluconazole; AMB, amphotericin B; CAS, caspofungin; R,resistant.

Finally, we evaluated the ability of the 2-aryloxazoline compounds to inhibit the growth of two genera of pathogenic fungi, Cryptococcus and Aspergillus. As shown in Supporting Information, Table S2, the 2-aryloxazolines showed moderate activity against Cryptococcus spp. (MIC: 0.25 to >16 μg/mL) and reduced antifungal activity against Aspergillus spp. (MIC: 1 to >16 μg/mL), when compared to the MIC values obtained toward Candida spp. (Tables 1 and 2 and Supporting Information, Table S1). Notably, among the 26 novel 2-aryloxazoline compounds, compounds 4i and 9i exhibited the most remarkable inhibitory effect on Candida, Cryptococcus, and Aspergillus growth (Table 1 and Supporting Information, Tables S1 and S2). It should be pointed out that unlike the fungistatic action on Candida spp. and Aspergillus spp. (MFC > 16 μg/mL), the fungicidal effect was only observed against Cryptococcus spp. (MFC: 1 to >16 μg/mL) (Supporting Information, Table S2).

It is important to emphasize that previously reported 2-oxazolines were effective against filamentous and yeast fungi but exhibited MIC values and cytotoxicities that were greater than those obtained in our study. Notably, the inhibitory efficacy exhibited by our 2-aryloxazoline compounds are comparable to other potential antifungals that have been reported to be effective against Candida spp., Cryptococcus spp., and Aspergillus spp.4,27

In conclusion, the present study describes short synthetic routes for producing novel 2-aryloxazolines. Some of the obtained compounds displayed antifungal activity with SIs that are considered safe. We found that the 2-oxazoline moiety is a determinant for antifungal activity, and the substituents in the lateral chains, as well as the addition of aromatic and electron-rich groups to the carboxyl group lateral chain, are essential for improving the inhibitory effect. Compounds 4i and 9i exhibit a broad spectrum of antifungal action and low cytotoxicity and thus represent promising lead molecules for the development of antifungal drugs for the treatment of cutaneous and systemic fungal infections.

Acknowledgments

We are grateful to the Laboratory of Medical Mycology of the Institute of Tropical Medicine of São Paulo (IMT-USP, São Paulo/SP, Brazil) and the National Institute for Quality and Safety Control (INCQS, Fiocruz, Rio de Janeiro/RJ, Brazil) for providing kindly the CBS and ATCC fungal isolates. We acknowledge support from the National Council for Scientific and Technological Development (CNPq, 405556/2018-7), São Paulo Research Foundation (FAPESP, 2017/19374-9 and 2018/11612-0), and Coordination for the Improvement of Higher Education Personnel (CAPES, Financial Code 001). K.I. is a research fellow of the CNPQ (grant 303373/2019-9).

Glossary

Abbreviations

AMB

amphotericin B

CAS

caspofungin

CC50

cytotoxic concentration of 50%

HA50

hemolytic activity of 50%

RBC

red blood cells

FLC

fluconazole

MIC

minimum inhibitory concentration

SI

selectivity index

Supporting Information Available

The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acsmedchemlett.0c00449.

  • Additional tables, synthetic and biological procedures, and NMR spectra data (PDF)

Author Contributions

L.M.Z.A., C.B.S., and M.P.D. synthesized the 2-aryloxazoline compounds and interpreted the chemical data. K.I. and V.M.B. performed all biological assays. K.I. and H.A.S. designed and wrote the manuscript. All authors approved the final version of the manuscript before submission.

The authors declare no competing financial interest.

Supplementary Material

ml0c00449_si_001.pdf (198KB, pdf)

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Associated Data

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Supplementary Materials

ml0c00449_si_001.pdf (198KB, pdf)

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