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Article

Design, Synthesis and Antifungal Activity of Novel Benzofuran-Triazole Hybrids

by
Zhen Liang
1,
Hang Xu
1,
Ye Tian
1,
Mengbi Guo
1,
Xin Su
2 and
Chun Guo
1,*
1
Key Laboratory of Structure-Based Drugs Design & Discovery of Ministry of Education, Shenyang Pharmaceutical University, Shenyang 110016, China
2
School of Life Sciences and Biopharmaceutics, Shenyang Pharmaceutical University, Shenyang 110016, China
*
Author to whom correspondence should be addressed.
Molecules 2016, 21(6), 732; https://doi.org/10.3390/molecules21060732
Submission received: 20 April 2016 / Revised: 27 May 2016 / Accepted: 1 June 2016 / Published: 7 June 2016
(This article belongs to the Collection Heterocyclic Compounds)
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Abstract

:
A series of novel benzofuran-triazole hybrids was designed and synthesized by click chemistry, and their structures were characterized by HRMS, FTIR and NMR. The in vitro antifungal activity of target compounds was evaluated using the microdilution broth method against five strains of pathogenic fungi. The result indicated that the target compounds exhibited moderate to satisfactory activity. Furthermore, molecular docking was performed to investigate the binding affinities and interaction modes between the target compound and N-myristoyltransferase. Based on the results, preliminary structure activity relationships (SARs) were summarized to serve as a foundation for further investigation.

1. Introduction

Fungal infections have posed a continuous and serious threat to human health and life during the past two decades, especially among hosts, such as patients undergoing anticancer chemotherapy or organ transplants, and patients with AIDS [1,2]. Clinically, available antifungal drugs have several drawbacks, such as drug-related toxicity, non-optimal pharmacokinetics, and the emergence of drug resistance [3,4]. Therefore, the development of new antifungal drugs with novel modes of action is required.
N-Myristoyltransferase (NMT) is a monomeric enzyme that catalyzes the transfer of the myristoyl group of myristoyl-CoA to the N-terminal glycine of various eukaryotic cellular proteins [5,6] and it was proven to be essential for the viability of pathogenic fungi, such as C. albicans [7] and C. neoformans [8]. Although NMT is also distributed in mammalian cells, there are clear differences in the peptide-substrate specificity between human and fungal NMT [9], which could be exploited to avoid adverse events caused by inhibiting human NMT. Therefore, NMT would be a promising target for the development of novel fungicidal drugs. Up to now, various types of NMT inhibitors such as peptidomimetic [10,11,12], myristic acid analogues [13] and different kinds of heterocycles [14,15,16] have been reported. Among them, benzofuran inhibitors showed high selectivity and powerful antifungal activity [16,17,18,19] (Figure 1). Furthermore, the benzofuran core itself possessed a definite antifungal activity and numbers of benzofuran derivatives were reported without indicating the targets [20,21,22,23] (Figure 1).
In recent years, the 1,2,3-triazole scaffold became a highlight fragment with the emergence of click chemistry and the 1,2,3-triazole–containing compounds were reported to possess a variety of biological activities [24,25,26,27,28], especially as antifungal agents [29,30,31]. Furthermore, the hybridizations of the 1,2,3-triazole moiety with other antifungal agents were reported. Coumarin derivatives incorporating the 1,2,3-triazole moiety showed antifungal activity [32]. Hybrids of fluconazole with 1,2,3-triazole were proved to possess satisfactory activity [33].
Encouraged by the results above, we attempted to design and synthesize a series of benzofuran-triazole hybrids to evaluate the in vitro antifungal activity.

2. Results and Discussion

2.1. Chemistry

The synthetic route to target compounds was outlined in Scheme 1. The reaction of 2′,6′-dihydroxyacetophenone with the corresponding 2-bromoacetophenone in a modified Rap-Stormer reaction condition [22] gave the benzofuran scaffold (1). Alkylation of the hydroxyl group of 1a,b with propargyl bromide gave terminal alkyne derivatives (2a,b). The aromatic azides (3a–i) were prepared from the corresponding anilines following the Sandmeyer conditions [27,31]. Finally, employing click chemistry, compounds 2a,b were cyclized with 3a–i, respectively, to give target compounds 4a–r in good yields.

2.2. Antifungal Activity

The in vitro antifungal activity of the target compounds was measured by means of the minimal inhibitory concentrations (MICs) with fluconazole as the control drug. The results are summarized in Table 1. Against fluconazole-resistant Trichophyton rubrum, many target compounds (4e,f, 4h and 4b–r) showed better activity than fluconazole (128 μg·mL−1) in the range of 32 to 64 μg·mL−1, and some compounds (4b, 4d, 4g, and 4i–l) showed equivalent activity to fluconazol. Except compounds 4a and 4c, most of the compounds showed antifungal activity against Cryptococcus neoformans in concentrations ranging from 32 to 128 μg·mL−1. The target compounds (4f, 4h, 4m, 4p and 4r) showed antifungal activity against Candida zeylanoides at the concentration of 64 μg·mL−1. Some compounds showed weak activity merely against Candida albicans (4f, 4h, 4m, 4o and 4r) and Rhodotorula rubra (4d, 4f, 4h, 4o and 4q,r) at the concentration of 128 μg·mL−1.
Observing the antifungal assay results, it can be noticed that the derivatives with a di-fluorine-substituted phenyl ring at the benzofuran C-2 side chain (ring A) are more effective than the mono-fluorine ones (e.g., 4f vs. 4o). Meanwhile, the substituted groups on the phenyl ring linked to the triazole (ring B) also had an impact on the activity. The alkyl-substituted compounds are more potent than the halogenated derivatives (e.g., 4b vs. 4f) and the ortho-substituted derivatives are more potent than the para isomers (e.g., 4e vs. 4f, 4j vs. 4k). The preliminary structure activity relationships (SARs) were supported by the outstanding bioactivities of 4o and 4r among all the target compounds.

2.3. Molecule Docking

In an attempt to investigate the action modes of the target compounds, 4o was docked into the crystal structure of NMT from C. albicans (CaNMT, PDB ID: 1IYL) using Discovery Studio 3.0. The docking results are illustrated in Figure 2. The benzofuran ring was located at the center of the active site, surrounding some hydrophobic residues, such as Tyr225, Tyr354 and Leu394, and forming a pi-pi interaction with Tyr225. The di-fluorine phenyl fragment formed a hydrophobic interaction with Phe115, Phe240 and Phe339. The phenyl triazole side chain stretched into the hydrophobic pocket constituted by Phe117, Tyr119 and Phe176. The oxygen atom of the benzofuran ring formed a hydrogen bond with His227. The interaction mode between 4o and the receptor is similar to the co-crystal ligand. On the other hand, no hydrogen bond was observed between triazole and Leu451, which is formed between the C-4 secondary amine of the co-crystal ligand. This hydrogen bond is important to the antifungal activity [34]. The docking result is supported by the weak antifungal activity against C. albicans of the target compounds.

3. Experimental Section

3.1. Chemistry

The 1H- and 13C-NMR spectra were recorded respectively on a Bruker AV-600 spectrometer and a Bruker AV-400 spectrometer. Chemical shifts were reported in parts per million (ppm, δ) downfield from TMS as an internal standard. High-resolution mass spectra (HRMS) were measured with an Agilent Accurate-Mass Q-TOF 6530 in ESI mode (Agilent, Santa Clara, CA, USA). FTIR spectra were recorded on a Bruker IFS 55 spectrometer (Bruker Co., Karlsruhe, Germany). Melting points (m.p.) were determined on an X-4 microscope melting point apparatus (Beijing Tech instrument Co., Ltd., Beijing, China) without calibration.

3.1.1. General Procedure for the Synthesis of Compounds 1a,b

The 2′,6′-Dihydroxyacetophenone (7.60 g, 50 mmol), potassium carbonate (8.30 g, 60 mol) and substituted 4-bromoacetylbenzene (50 mmol) were refluxed in 80 mL acetonitrile for six hours. After cooled to room temperature, the reaction mixture was poured into water. The crude products were filtrated and crystallized from ethanol.
2-(4-Fluorobenzoyl)-3-methyl-4-hydroxybenzofuran (1a): Yellow solid; yield 58%. 1H-NMR (600 MHz, DMSO-d6) δ 10.51 (s, 1H), 8.04 (dd, J = 8.5, 5.6 Hz, 2H), 7.39 (t, J = 8.7 Hz, 2H), 7.30 (t, J = 8.1 Hz, 1H), 7.03 (d, J = 7.9 Hz, 1H), 6.68 (d, J = 7.9 Hz, 1H), 2.70 (s, 3H). 13C-NMR (151 MHz, DMSO) δ 183.72, 165.78, 164.12, 155.81, 155.22, 146.39, 134.61, 132.58, 132.51, 130.15, 128.01, 117.89, 115.99, 115.85, 108.47, 103.14, 12.01. IR (KBr, cm−1): 3423, 2924, 1623, 1604, 1385, 1269, 1054. ESI–HRMS (m/z) found: 269.0619 (calcd. for C16H10FO3 [M − H]−: 269.0619).
2-(2,4-Difluorobenzoyl)-3-methyl-4-hydroxybenzofuran (1b): Yellow solid; yield 62%. 1H-NMR (600 MHz, DMSO-d6) δ 10.57 (s, 1H), 7.78–7.71 (m, 1H), 7.46–7.43 (m, 1H), 7.33–7.23 (m, 2H), 6.97 (d, J = 7.9 Hz, 1H), 6.67 (d, J = 7.9 Hz, 1H), 2.67 (s, 3H). 13C-NMR (151 MHz, DMSO) δ 181.82, 165.34, 163.67, 156.06, 155.45, 146.27, 132.47, 130.71, 128.14, 118.05, 112.61, 112.45, 108.47, 103.07, 11.67. IR (KBr, cm−1): 3417, 2925, 1614, 1385, 1269, 1054. ESI-HRMS (m/z) found: 287.0531 (calcd. for C16H9F2O3 [M − H]−: 287.0525).

3.1.2. General Procedure for the Synthesis of Compounds 2a,b

To a solution of compound 1a or 1b (10.0 mmol) in DMF (20 mL), propargyl bromide (1.30 g, 10.9 mmol) and potassium carbonate (1.70 g, 12.3 mmol) were added. The reaction mixture was stirred at room temperature for 5 h, and was then diluted with ethyl acetate (80 mL) and washed with water (2 × 100 mL). The organic layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude products were used without purification.
2-(4-Fluorobenzoyl)-3-methyl-4-(propyn-3-yloxy)benzofuran (2a): Yellow solid; yield 62%. 1H-NMR (600 MHz, DMSO-d6) δ 8.07–8.04 (m, 2H), 7.48 (t, J = 8.2 Hz, 1H), 7.43–7.36 (m, 2H), 7.26 (d, J = 8.3 Hz, 1H), 6.93 (d, J = 8.1 Hz, 1H), 4.98 (d, J = 2.4 Hz, 2H), 3.66 (t, J = 2.4 Hz, 1H), 2.69 (s, 3H). 13C-NMR (151 MHz, DMSO) δ 183.80, 165.88, 164.21, 155.27, 154.47, 146.86, 134.46, 132.67, 132.61, 130.01, 127.15, 118.69, 116.04, 115.90, 106.11, 105.87, 79.16, 56.62, 11.99. IR (KBr, cm−1): 3298, 2925, 2115, 1642, 1601, 1501, 1271, 1257, 1236, 1089. ESI-HRMS (m/z) found: 331.0741 (calcd. for C19H13FO3Na [M + Na]+: 331.0741).
2-(2,4-Difluorobenzoyl)-3-methyl-4-(propyn-3-yloxy)benzofuran (2b): Yellow solid; yield 55%. 1H-NMR (600 MHz, DMSO-d6) δ 7.77 (td, J = 8.3, 6.5 Hz, 1H), 7.50–7.44 (m, 2H), 7.28 (td, J = 8.5, 2.5 Hz, 1H), 7.20 (d, J = 8.4 Hz, 1H), 6.92 (d, J = 8.1 Hz, 1H), 4.98 (d, J = 2.4 Hz, 2H), 3.66 (t, J = 2.4 Hz, 1H), 2.68 (s, 3H). 13C-NMR (151 MHz, DMSO) δ 181.95, 165.39, 163.80, 155.50, 154.65, 146.70, 132.62, 130.57, 127.26, 124.06, 118.80, 112.66, 112.50, 106.15, 105.79, 79.21, 56.66, 11.67. IR (KBr, cm−1): 3239, 2116, 1641, 1612, 1499, 1086. ESI-HRMS (m/z) found: 349.0646 (calcd. for C19H12F2O3Na [M + Na]+: 349.0647).

3.1.3. General Procedure for the Synthesis of Compounds 4a–r

Compound 2a (305 mg, 1 mmol), CuSO4·5H2O (50 mg, 0.2 mmol) and 4-chloroazidobenzene (135 mg, 1 mmol) were dissolved in 10 mL DMF, and sodium ascorbate (99 mg, 0.5 mmol) was added. The reaction mixture was stirred at room temperature for 3 h, then was poured into water. The crude product was filtered, which was purified by silica gel column chromatography (PET/EtOAc = 2:1, v/v) to give target compound 4a as yellow solid; yield 72%; m.p.: 168–170 °C. 1H-NMR (600 MHz, DMSO-d6) δ 9.02 (s, 1H), 8.04 (dd, J = 8.4, 5.7 Hz, 2H), 7.96 (d, J = 8.7 Hz, 2H), 7.66 (d, J = 8.7 Hz, 2H), 7.48 (t, J = 8.2 Hz, 1H), 7.38 (t, J = 8.7 Hz, 2H), 7.25 (d, J = 8.4 Hz, 1H), 7.09 (d, J = 8.1 Hz, 1H), 5.41 (s, 2H), 2.65 (s, 3H); 13C-NMR (101 MHz, DMSO) δ 183.85, 155.41, 155.32, 146.88, 144.22, 135.77, 133.55, 132.76, 132.66, 130.35, 130.32, 127.51, 123.33, 122.31, 118.74, 116.17, 115.95, 106.08, 105.78, 62.24, 12.13; IR (KBr, cm−1): 2925, 1635, 1599, 1553, 1502, 1271, 1252, 1087. ESI–HRMS (m/z) found: 484.0841 (calcd. for C25H17ClFN3O3Na [M + Na]+: 484.0835).
The compounds 4b–r were synthesized using the same operation procedure of compound 4a.
Compound 4b: Yellow solid; yield 79%; m.p.: 169–170 °C. 1H-NMR (600 MHz, DMSO-d6) δ 8.78 (s, 1H), 8.07–8.02 (m, 2H), 7.78 (dd, J = 8.0, 1.4 Hz, 1H), 7.73 (dd, J = 7.8, 1.7 Hz, 1H), 7.64 (td, J = 7.8, 1.7 Hz, 1H), 7.59 (td, J = 7.7, 1.4 Hz, 1H), 7.50 (t, J = 8.2 Hz, 1H), 7.40 (t, J = 8.8 Hz, 2H), 7.26 (d, J = 8.4 Hz, 1H), 7.12 (d, J = 8.1 Hz, 1H), 5.44 (s, 2H), 2.65 (s, 3H). 13C-NMR (101 MHz, DMSO) δ 183.88, 155.41, 146.90, 143.10, 134.90, 134.59, 132.76, 132.67, 132.22, 131.04, 130.33, 129.00, 128.90, 127.50, 127.28, 118.78, 116.18, 115.96, 106.24, 105.79, 62.37, 12.06. IR (KBr, cm−1): 2923, 1638, 1598, 1556, 1500, 1272, 121232, 1091. ESI-HRMS (m/z) found: 484.0844 (calcd. for C25H17ClFN3O3Na [M + Na]+: 484.0835).
Compound 4c: Yellow solid; yield 76%; m.p.: 172–174 °C. 1H-NMR (600 MHz, DMSO-d6) δ 9.04 (s, 1H), 8.04 (dd, J = 8.5, 5.6 Hz, 2H), 7.90 (d, J = 8.8 Hz, 2H), 7.80 (d, J = 8.8 Hz, 2H), 7.49 (t, J = 8.2 Hz, 1H), 7.39 (t, J = 8.8 Hz, 2H), 7.25 (d, J = 8.4 Hz, 1H), 7.10 (d, J = 8.0 Hz, 1H), 5.42 (s, 2H), 2.65 (s, 3H). 13C-NMR (101 MHz, DMSO) δ 183.87, 155.32, 146.88, 144.23, 136.18, 133.28, 132.76, 132.67, 130.33, 127.51, 123.31, 122.55, 121.93, 118.74, 116.17, 115.96, 106.09, 105.79, 62.24, 40.61, 12.14. IR (KBr, cm−1): 2924, 1633, 1600, 1550, 1498, 1270, 1251, 1087. ESI-HRMS (m/z) found: 506.0515 (calcd. for C25H18BrFN3O3 [M + H]+: 506.0516).
Compound 4d: Yellow solid; yield 81%; m.p.: 166–169 °C. 1H-NMR (600 MHz, DMSO-d6) δ 8.75 (s, 1H), 8.05 (dd, J = 8.6, 5.6 Hz, 2H), 7.93–7.90 (m, 1H), 7.68 (dd, J = 7.8, 1.3 Hz, 1H), 7.64–7.61 (m, 1H), 7.58–7.54 (m, 1H), 7.50 (t, J = 8.2 Hz, 1H), 7.40 (t, J = 8.8 Hz, 2H), 7.26 (d, J = 8.3 Hz, 1H), 7.12 (d, J = 8.1 Hz, 1H), 5.44 (s, 2H), 2.66 (s, 3H). 13C-NMR (101 MHz, DMSO) δ 183.87, 155.40, 146.89, 143.02, 136.58, 134.58, 134.11, 132.76, 132.67, 132.52, 130.33, 129.46, 129.20, 127.53, 127.25, 119.34, 118.78, 116.17, 115.95, 106.23, 105.77, 62.40, 12.09. IR (KBr, cm−1): 2923, 1638, 1614, 1598, 1555, 1500, 1271, 1255, 1090. ESI–HRMS (m/z) found: 506.0520 (calcd. for C25H18BrFN3O3 [M + H]+: 506.0516).
Compound 4e: Yellow solid; yield 77%; m.p.: 160–161 °C. 1H-NMR (600 MHz, DMSO-d6) δ 8.96 (s, 1H), 8.04 (dd, J = 8.7, 5.6 Hz, 2H), 7.80 (d, J = 8.4 Hz, 2H), 7.49 (t, J = 8.2 Hz, 1H), 7.39 (m, J = 8.8, 4.7 Hz, 4H), 7.25 (d, J = 8.4 Hz, 1H), 7.10 (d, J = 8.1 Hz, 1H), 5.41 (s, 2H), 2.66 (s, 3H), 2.37 (s, 3H). 13C-NMR (101 MHz, DMSO) δ 183.85, 155.36, 146.87, 143.91, 138.90, 134.74, 134.55, 132.75, 132.66, 130.71, 130.32, 127.53, 123.12, 120.47, 118.73, 116.16, 115.94, 106.07, 105.74, 62.30, 21.05, 12.13. IR (KBr, cm−1): 2925, 1637, 1599, 1553, 1499, 1271, 1254, 1088. ESI-HRMS (m/z) found: 464.1393 (calcd. for C26H20FN3O3Na [M + Na]+: 464.1386).
Compound 4f: Yellow solid; yield 80%; m.p.: 154–156 °C. 1H-NMR (600 MHz, DMSO-d6) δ 8.69 (s, 1H), 8.10–7.99 (m, 2H), 7.51–7.45 (m, 4H), 7.40 (q, J = 8.7 Hz, 3H), 7.26 (d, J = 8.5 Hz, 1H), 7.12 (d, J = 8.1 Hz, 1H), 5.43 (s, 2H), 2.65 (s, 3H), 2.13 (s, 3H). 13C-NMR (101 MHz, DMSO) δ 183.87, 166.37, 163.87, 155.41, 146.88, 143.08, 136.66, 134.55, 133.54, 132.76, 132.67, 131.84, 130.34, 127.50, 126.66, 126.52, 118.77, 116.17, 115.95, 106.18, 105.75, 62.50, 17.78, 12.04. IR (KBr, cm−1): 2925, 1639, 1624, 1599, 1544, 1501, 1271, 1250, 1234, 1089. ESI-HRMS (m/z) found: 464.1394 (calcd. for C26H20FN3O3Na [M + Na]+: 464.1386).
Compound 4g: Yellow solid; yield 78%; m.p.: 155–158 °C. 1H-NMR (600 MHz, DMSO-d6) δ 8.67 (s, 1H), 8.04 (dd, J = 8.8, 5.6 Hz 2H), 7.54 (m, 1H), 7.51–7.47 (m, 2H), 7.42 (dd, J = 4.3, 1.5 Hz, 2H), 7.41–7.35 (m, 2H), 7.26 (d, J = 8.3 Hz, 1H), 7.11 (d, J = 8.1 Hz, 1H), 5.43 (s, 2H), 2.64 (s, 3H), 2.41 (q, J = 7.6 Hz, 2H), 0.96 (t, J = 7.6 Hz, 3H). 13C-NMR (101 MHz, DMSO) δ 183.86, 166.37, 163.88, 155.40, 146.90, 143.11, 139.81, 136.13, 134.58, 132.76, 132.66, 130.75, 130.38, 130.31, 127.49, 126.96, 118.80, 116.17, 115.95, 106.24, 105.74, 62.50, 24.27, 15.17, 11.99. IR (KBr, cm−1): 2925, 1626, 1598, 1541, 1501, 1269, 1249, 1088. ESI-HRMS (m/z) found: 456.1719 (calcd. for C27H23FN3O3 [M + H]+: 456.1723).
Compound 4h: Yellow solid; yield 71%; m.p.: 156–159 °C. 1H-NMR (600 MHz, DMSO-d6) δ 8.58 (s, 1H), 8.04 (dd, J = 8.7, 5.6 Hz, 2H), 7.49 (t, J = 8.2 Hz, 1H), 7.45–7.34 (m, 3H), 7.29 (d, J = 7.6 Hz, 2H), 7.25 (d, J = 8.4 Hz, 1H), 7.09 (d, J = 8.0 Hz, 1H), 5.44 (s, 2H), 2.62 (s, 3H), 1.91 (s, 6H). 13C-NMR (101 MHz, DMSO) δ 183.86, 155.39, 146.90, 143.12, 136.22, 135.30, 134.57, 132.76, 132.67, 130.48, 130.30, 128.87, 127.46, 126.98, 118.80, 116.17, 115.95, 106.28, 105.74, 62.65, 17.24, 11.88. IR (KBr, cm−1): 2924, 1640, 1599, 1551, 1501, 1271, 1255, 1101, 1042. ESI-HRMS (m/z) found: 456.1716 (calcd. for C27H23FN3O3 [M + H]+: 456.1723).
Compound 4i: Yellow solid; yield 70%; m.p.: 157–158 °C. 1H-NMR (600 MHz, DMSO-d6) δ 8.63 (s, 1H), 8.04 (dd, J = 8.7, 5.6 Hz, 2H), 7.49 (t, J = 8.2 Hz, 1H), 7.43–7.36 (m, 2H), 7.33 (d, J = 8.0 Hz, 1H), 7.28 (d, J = 1.8 Hz, 1H), 7.26 (d, J = 8.4 Hz, 1H), 7.20 (dd, J = 8.0, 1.9 Hz, 1H), 7.11 (d, J = 8.1 Hz, 1H), 5.42 (s, 2H), 2.65 (s, 3H), 2.35 (s, 3H), 2.08 (s, 3H). 13C-NMR (101 MHz, DMSO) δ 183.85, 163.87, 155.42, 146.88, 142.99, 140.02, 134.57, 134.29, 133.19, 132.76, 132.66, 132.23, 130.32, 127.89, 127.51, 126.66, 126.30, 118.77, 116.17, 115.95, 106.17, 105.73, 62.50, 21.10, 17.68, 12.03. IR (KBr, cm−1): 2925, 1639, 1600, 1553, 1502, 1270, 1255, 1101. ESI-HRMS (m/z) found: 456.1713 (calcd. for C27H23FN3O3 [M + H]+: 456.1723).
Compound 4j: Yellow solid; yield 82%; m.p.: 168–171 °C. 1H-NMR (600 MHz, DMSO-d6) δ 9.04 (s, 1H), 7.99–7.94 (m, 2H), 7.75 (td, J = 8.4, 6.5 Hz, 1H), 7.69–7.64 (m, 2H), 7.49 (t, J = 8.2 Hz, 1H), 7.45 (td, J = 10.3, 2.3 Hz, 1H), 7.27 (td, J = 8.4, 2.2 Hz, 1H), 7.20 (d, J = 8.4 Hz, 1H), 7.09 (d, J = 8.1 Hz, 1H), 5.42 (s, 2H), 2.64 (s, 3H). 13C-NMR (101 MHz, DMSO) δ 182.80, 156.45, 15631, 147.55, 144.98, 136.58, 134.35, 133.46, 131.68, 131.16, 128.44, 124.15, 123.12, 119.66, 113.39, 106.91, 106.50, 106.35, 106.09, 105.83, 63.08, 12.62. IR (KBr, cm−1): 2924, 1635, 1600, 1551, 1502, 1271, 1252, 1088. ESI-HRMS (m/z) found: 480.0917 (calcd. for C25H17ClF2N3O3 [M + H]+: 480.0927).
Compound 4k: Yellow solid; yield 78%; m.p.: 166–168 °C. 1H-NMR (600 MHz, DMSO-d6) δ 8.78 (s, 1H), 7.80–7.75 (m, 2H), 7.73 (dd, J = 7.8, 1.7 Hz, 1H), 7.64 (td, J = 7.8, 1.6 Hz, 1H), 7.59 (t, J = 7.6 Hz, 1H), 7.50 (t, J = 8.2 Hz, 1H), 7.46 (td, J = 10.3, 2.2 Hz,1H), 7.27 (td, J = 8.5, 2.2 Hz,1H), 7.21 (d, J = 8.4 Hz, 1H), 7.12 (d, J = 8.1 Hz, 1H), 5.45 (s, 2H), 2.63 (s, 3H). 13C-NMR (101 MHz, DMSO) δ 181.99, 155.64, 155.56, 146.75, 143.06, 134.89, 132.22, 131.03, 130.88, 129.01, 128.98, 128.90, 127.62, 127.28, 118.90, 112.79, 112.57, 106.27, 105.70, 105.55, 105.29, 105.03, 62.41, 11.73. IR (KBr, cm−1): 2923, 1642, 1613, 1560, 1497, 1268, 1091. ESI-HRMS (m/z) found: 480.0923 (calcd. for C25H17ClF2N3O3 [M + H]+: 480.0927).
Compound 4l: Yellow solid; yield 78%; m.p.: 167–170 °C. 1H-NMR (600 MHz, DMSO-d6) δ 9.03 (s, 1H), 7.90 (d, J = 8.4 Hz, 2H), 7.81 (d, J = 8.4 Hz, 2H), 7.75 (q, J = 7.8 Hz, 1H), 7.49 (t, J = 8.3 Hz, 1H), 7.45 (t, J = 9.5 Hz, 1H), 7.31–7.23 (m, 1H), 7.20 (d, J = 8.4 Hz, 1H), 7.10 (d, J = 8.1 Hz, 1H), 5.42 (s, 2H), 2.64 (s, 3H). 13C-NMR (101 MHz, DMSO) δ 181.99, 155.64, 155.50, 146.74, 144.20, 136.18, 133.27, 130.87, 127.63, 123.29, 122.55, 121.93, 118.85, 112.79, 112.56, 106.12, 105.70, 105.55, 105.28, 105.02, 62.28, 11.81. IR (KBr, cm−1): 2925, 1648, 1612, 1565, 1498, 1270, 1254, 1085. ESI-HRMS (m/z) found: 546.0235 (calcd. for C25H16BrF2N3O3Na [M + Na]+: 546.0235).
Compound 4m: Yellow solid; yield 80%; m.p.: 166–169 °C. 1H-NMR (600 MHz, DMSO-d6) δ 8.74 (s, 1H), 7.92 (d, J = 8.0 Hz, 1H), 7.79–7.73 (m, 1H), 7.68 (dd, J = 7.8, 1.6 Hz, 1H), 7.62 (t, J = 7.6 Hz, 1H), 7.56 (t, J = 7.7 Hz, 1H), 7.50 (t, J = 8.2 Hz, 1H), 7.45 (td, J = 10.0, 2.4 Hz, 1H), 7.27 (td, J = 8.5, 2.4 Hz, 1H), 7.20 (d, J = 8.4 Hz, 1H), 7.12 (d, J = 8.1 Hz, 1H), 5.45 (s, 2H), 2.64 (s, 3H). 13C-NMR (101 MHz, DMSO) δ 181.99, 162.75, 155.57, 146.75, 142.98, 136.58, 134.11, 132.52, 130.89, 129.46, 129.20, 127.65, 127.26, 119.35, 118.90, 112.78, 112.57, 106.27, 105.69, 105.55, 105.29, 105.02, 62.44, 11.76. IR (KBr, cm−1): 2924, 1645, 1613, 1597, 1560, 1266, 1253, 1086. ESI-HRMS (m/z) found: 546.0238 (calcd. for C25H16BrF2N3O3Na [M + Na]+: 546.0235).
Compound 4n: Yellow solid; yield 78%; m.p.: 164–166 °C. 1H-NMR (600 MHz, DMSO-d6) δ 8.95 (s, 1H), 7.79 (d, J = 8.4 Hz, 2H), 7.75 (m, J = 8.3 Hz, 1H), 7.49 (t, J = 8.2 Hz, 1H), 7.45 (td, J = 10.4, 2.3 Hz, 1H), 7.39 (d, J = 8.1 Hz, 2H), 7.27 (td, J = 8.5, 2.5 Hz, 1H), 7.19 (d, J = 8.4 Hz, 1H), 7.10 (d, J = 8.1 Hz, 1H), 5.41 (s, 2H), 2.64 (s, 3H), 2.37 (s, 3H). 13C-NMR (101 MHz, DMSO) δ 181.98, 155.64, 155.54, 146.73, 143.88, 138.90, 134.74, 132.55, 130.87, 130.71, 127.64, 123.12, 120.48, 118.85, 112.76, 112.55, 106.10, 105.65, 105.28, 105.02, 62.34, 21.04, 11.80. IR (KBr, cm−1): 2325, 1649, 1612, 1564, 1498, 1271, 1256, 1086. ESI-HRMS (m/z) found: 460.1466 (calcd. for C26H20F2N3O3 [M + H]+: 460.1473).
Compound 4o: Yellow solid; yield 75%; m.p.: 165–168 °C. 1H-NMR (600 MHz, DMSO-d6) δ 8.69 (s, 1H), 7.94 (s, 1H), 7.76 (td, J = 8.3, 6.5 Hz, 1H), 7.51–7.40 (m, 5H) 7.27 (td, J = 8.5, 2.5 Hz, 1H), 7.20 (d, J = 8.4 Hz, 1H), 7.11 (d, J = 8.1 Hz, 1H), 5.43 (s, 2H), 2.64 (s, 3H), 2.13 (s, 3H). 13C-NMR (101 MHz, DMSO) δ 181.99, 162.75, 155.64, 155.59, 146.75, 143.04, 136.65, 133.54, 132.67, 131.83, 130.88, 130.37, 127.63, 127.50, 126.66, 126.52, 118.89, 112.77, 112.57, 106.22, 105.66, 105.29, 62.54, 17.77, 11.71. IR (KBr, cm−1): 2924, 1641, 1610, 1563, 1500, 1269, 1090, 1039. ESI-HRMS (m/z) found: 460.1468 (calcd. for C26H20F2N3O3 [M + H]+: 460.1473).
Compound 4p: Yellow solid; yield 85%; m.p.: 168–170 °C. 1H-NMR (600 MHz, DMSO-d6) δ 8.67 (s, 1H), 7.75 (td, J = 8.3, 6.5 Hz, 1H), 7.54 (td, J = 5.4, 5.0, 2.3 Hz, 1H), 7.51–7.48 (m, 2H), 7.47–7.43 (m, 1H), 7.42 (dd, J = 3.8, 1.2 Hz, 2H), 7.27 (td, J = 8.5, 2.5 Hz, 1H), 7.20 (d, J = 8.4 Hz, 1H), 7.11 (d, J = 8.1 Hz, 1H), 5.43 (s, 2H), 2.63 (s, 3H), 2.40 (q, J = 7.6 Hz, 2H), 0.95 (t, J = 7.6 Hz, 3H). 13C-NMR (101 MHz, DMSO) δ 182.00, 155.63, 155.56, 146.74, 143.06, 139.80, 136.12, 130.87, 130.74, 130.37, 127.61, 127.48, 126.98, 126.94, 118.91, 112.76, 112.55, 106.28, 105.66, 105.53, 105.28, 105.02, 62.53, 24.26, 15.16, 11.66. IR (KBr, cm−1): 2930, 1644, 1611, 1562, 1499, 1270, 1090. ESI-HRMS (m/z) found: 496.1453 (calcd. for C27H21F2N3O3Na [M + H]+: 496.1443).
Compound 4q: Yellow solid; yield 79%; m.p.: 165–168 °C. 1H-NMR (600 MHz, DMSO-d6) δ 8.58 (s, 1H), 7.79–7.72 (m, 1H), 7.49 (t, J = 8.2 Hz, 1H), 7.47–7.43 (m, 1H), 7.39 (t, J = 7.6 Hz, 1H), 7.30–7.25 (m, 3H), 7.20 (d, J = 8.4 Hz, 1H), 7.09 (d, J = 8.0 Hz, 1H), 5.44 (s, 2H), 2.61 (s, 3H), 1.90 (s, 6H). 13C-NMR (101 MHz, DMSO) δ 181.99, 159.32, 155.59, 146.76, 143.09, 136.21, 135.30, 130.85, 130.48, 128.87, 127.57, 126.97, 118.93, 112.78, 112.58, 106.34, 105.66, 105.54, 105.28, 105.03, 62.70, 17.24, 11.55. IR (KBr, cm−1): 2924, 1643, 1610, 1559, 1498, 1268, 1090. ESI-HRMS (m/z) found: 474.1613 (calcd. for C27H22F2N3O3 [M + H]+: 474.1629).
Compound 4r: Yellow solid; yield 79%; m.p.: 169–171 °C. 1H-NMR (600 MHz, DMSO-d6) δ 8.62 (s, 1H), 7.75 (q, J = 8.2 Hz, 1H), 7.49 (t, J = 8.2 Hz, 1H), 7.47–7.42 (m, 1H), 7.32 (d, J = 8.0 Hz, 1H), 7.28 (s, 2H), 7.20 (m, 2H), 7.11 (d, J = 8.1 Hz, 1H), 5.42 (s, 2H), 2.63 (s, 3H), 2.35 (s, 3H), 2.08 (s, 3H). 13C-NMR (101 MHz, DMSO) δ 181.99, 155.62, 146.74, 142.95, 140.02, 134.28, 133.18, 132.55, 132.23, 130.88, 127.89, 127.63, 126.67, 126.30, 118.89, 112.78, 112.56, 106.22, 105.65, 105.54, 105.28, 105.02, 62.54, 21.10, 17.67, 11.70. IR (KBr, cm−1): 2925, 1643, 1611, 1563, 1499, 1269, 1090. ESI-HRMS (m/z) found: 474.1623 (calcd. for C27H22F2N3O3 [M + H]+: 474.1629).

3.2. Antifungal Assay

Test fungal strains were obtained from China Pharmaceutical Culture Collection (Candida albicans CPCC400616), China General Microbiological Culture Collection Center (Cryptococcus neoformans CGMCC2.3161 and Candida zeylanoides CGMCC2.3739) or were clinical isolates (Trichophyton rubrum and Rhodotorula rubra).
The in vitro antifungal activity of target compounds was determined by the micro-broth dilution method in 96-well plates according to the CLSI M27-A3 guidelines [35]. Tested compounds and the control drug were dissolved in DMSO respectively and Tween-20 was added as a stabilizer. The prepared samples were serially two-fold diluted in growth medium, inoculated and incubated at 35 °C. The MICs were determined at 24 h for C. alb., C. zey., T. rub., and R. rub., and at 72 h for C. neo.

4. Conclusions

In summary, a series of benzofuran-triazoles hybrids has been designed and synthesized. The target compounds were characterized by HRMS, FTIR and NMR. The biological assay results indicated that most of the target compounds possessed in vitro antifungal activity against fluconazole-resistant Trichophyton rubrum and Cryptococcus neoformans. Several compounds (e.g., 4o and 4r) showed satisfactory activity, which makes them valuable for further research. Based on these results, preliminary SARs were summarized to serve as a foundation for the further investigation of antifungal drugs.

Acknowledgments

We greatly appreciate the funding support for this research provided by the National Natural Science Foundation of China (Grant No. 81573292).

Author Contributions

Zhen Liang designed and carried out the experiments and wrote the paper; Hang Xu, Ye Tian, Mengbi Guo assisted in experiments; Xin Su supervised and directed the biological assays; Chun Guo supervised the whole experiment and provided technical guidance. All authors have read and approved the final manuscript.

Conflicts of Interest

The authors declare no conflict of interest.

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  • Sample Availability: Samples of the compounds 1a,b, 2a,b and 4a–r are available from the authors.
Molecules 21 00732 g001 550
Figure 1. The representative structures of antifungal agents. (A) Representative structures of the benzofuran NMT inhibitors; (B) Representative benzofuran derivatives with antifungal activity; (C) Representative 1,2,3-triazole derivatives with antifungal activity.
Figure 1. The representative structures of antifungal agents. (A) Representative structures of the benzofuran NMT inhibitors; (B) Representative benzofuran derivatives with antifungal activity; (C) Representative 1,2,3-triazole derivatives with antifungal activity.
Molecules 21 00732 g001
Molecules 21 00732 sch001 550
Scheme 1. Synthesis of target compounds 4a–r. Reagents and conditions: (i) K2CO3/CH3CN/reflux 5–6 h; (ii) propargyl bromide/K2CO3/r.t. 3–5 h; (iii) CuSO4∙5H2O/sodium ascorbate/DMF/r.t. 2–4 h.
Scheme 1. Synthesis of target compounds 4a–r. Reagents and conditions: (i) K2CO3/CH3CN/reflux 5–6 h; (ii) propargyl bromide/K2CO3/r.t. 3–5 h; (iii) CuSO4∙5H2O/sodium ascorbate/DMF/r.t. 2–4 h.
Molecules 21 00732 sch001
Molecules 21 00732 g002 550
Figure 2. Molecule docking results.(A) The location of docking ligands; (B) Hydrogen bonds between 4o and receptor; (C) Hydrogen bonds between co-crystal ligand and receptor.
Figure 2. Molecule docking results.(A) The location of docking ligands; (B) Hydrogen bonds between 4o and receptor; (C) Hydrogen bonds between co-crystal ligand and receptor.
Molecules 21 00732 g002
Table
Table 1. Antifungal in vitro activities of the target compounds (MIC, μg·mL−1).
Molecules 21 00732 i001
Table 1. Antifungal in vitro activities of the target compounds (MIC, μg·mL−1).
Molecules 21 00732 i001
CompoundR1R2C. alb.C. neo.C. zey.T. rub.R. rub.
2aH >128>128>128>128>128
2bF >128>128>128>128>128
4aH4-Cl>128>128>128>128>128
4bH2-Cl>128128>128128>128
4cH4-Br>128>128>128>128>128
4dH2-Br>12812812864128
4eH4-CH3>128128>12864>128
4fH2-CH3128646464128
4gH2-C2H5>128128>128128>128
4hH2,6-di-CH31281286464128
4iH2,5-di-CH3>128128>128128>128
4jF4-Cl>128128>128128>128
4kF2-Cl>12864>128128>128
4lF4-Br>128128>128128>128
4mF2-Br128646464>128
4nF4-CH3>12864>12864>128
4oF2-CH31283212832128
4pF2-C2H5>128646464>128
4qF2,6-di-CH3>12812812864128
4rF2,5-di-CH3128646432128
FCZ 180.51288
Abbreviations: C. alb., Candida albicans (CPCC400616); C. neo., Cryptococcus neoformans (CGMCC2.3161); C. zey., Candida zeylanoides (CGMCC2.3739); T. rub., Trichophyton rubrum; R. rub., Rhodotorula rubra; FCZ, Fluconazole.

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MDPI and ACS Style

Liang, Z.; Xu, H.; Tian, Y.; Guo, M.; Su, X.; Guo, C. Design, Synthesis and Antifungal Activity of Novel Benzofuran-Triazole Hybrids. Molecules 2016, 21, 732. https://doi.org/10.3390/molecules21060732

AMA Style

Liang Z, Xu H, Tian Y, Guo M, Su X, Guo C. Design, Synthesis and Antifungal Activity of Novel Benzofuran-Triazole Hybrids. Molecules. 2016; 21(6):732. https://doi.org/10.3390/molecules21060732

Chicago/Turabian Style

Liang, Zhen, Hang Xu, Ye Tian, Mengbi Guo, Xin Su, and Chun Guo. 2016. "Design, Synthesis and Antifungal Activity of Novel Benzofuran-Triazole Hybrids" Molecules 21, no. 6: 732. https://doi.org/10.3390/molecules21060732

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