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Natural phenolic derivatives based on piperine scaffold as potential antifungal agents

Natural phenolic derivatives based on piperine scaffold as potential antifungal agents Piperine is a natural alkaloid with a wide range of biological functions. Natural phenolic compounds existed in many essential oils (EOs) are plant-derived aroma compounds with broad range of biological activities, however, their actions are slow, and they are typically unstable to light or heat, difficult to extract and so on. In order to find high- potential fungicides derived from piperine, a series of piperine-directed essential oil derivatives were designed and 1 13 synthesized. The structures of all molecules were confirmed by satisfied spectral data, including H NMR, C NMR and ESIMS. The target compounds were screened for their potential fungicidal activities against six species of plant patho- gen fungi, including Rhizoctonia solani, Fusarium graminearum, Phomopsis adianticola, Alternaria tenuis Nees, Phytoph- thora capsici and Gloeosporium theae-sinensis. Some of target compounds exhibited moderate and broad-spectrum activity against tested fungi compared to the parental piperine. Further studies have shown that some different concentrations of compounds have significant inhibitory activity against Alternaria tenuis Nees and Phytophthora capsici compared to commercial carbendazim, and compound 2b exhibited particularly significant broad-spectrum fungicidal activity. Keywords: Piperine, Essential oils, Synthesis, Fungicidal activity Introduction and intermediate [11]. Its structure is mainly divided into Piperine, a natural amide compound, is the main active three parts: piperidine ring, aromatic heterocyclic ring, substance extracted of Piper nigrum Linn. As an impor- and aliphatic hydrocarbon chain. These three places are tant natural alkaloid, piperine exhibited a wide spectrum usually considered by the researchers to be essential for of biological and pharmacological activities [1–6], it has their biological activity, and by modifying the structure of anti-oxidation, antidepressant [7], toxic effect against these parts, the biological activity of the compounds can be changed. hepatocytes [8], antiapoptotic efficacy [9], high immu - Essential oils (EOs) are class of complex mixtures of nomodulatory and antitumor activity [4], and has obvi- low molecular weight compounds extracted from vari ous effects in lowering blood fat [10]. Clinically, it can - effectively control the incidence of hyperlipidemia, the ous plants by steam distillation and various solvents [12]. treatment rate is as high as 93.3%, and it can also reduce Plant essential oils have received extensive attention from the incidence of cardiovascular and cerebrovascular dis- plant protection experts in recent years due to their low eases. In addition to being used as a medicine, piperine toxicity to mammals, low residue and extensive biologi- is also an important organic synthetic building blocks cal activity [13–15]. At present, there are many varieties of plant essential oils, and their applications are limited to the contact, fumigation and repellent of pests in con- *Correspondence: caoxiufang@mail.hzau.edu.cn College of Science, Huazhong Agricultural University, Wuhan 430070, fined environments such as greenhouses and warehouses China [16–18]. In addition, essential oils can also be used as © The Author(s) 2020. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creat iveco mmons .org/licen ses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creat iveco mmons .org/publi cdoma in/ zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data. Wang et al. BMC Chemistry (2020) 14:24 Page 2 of 12 synergists, solubilizers, flavoring agents and chemi - General synthesis of precursors cal pesticides. However, most of essential oils are vola- The key precursors including (E)-3-(benzo[d][1,3]dioxol- tile, unstable to light and heat, easy to decompose, etc. 5-yl)acrylic acid (n = 1) and piperic acid (n = 2) were pre- Therefore, if the rational derivatization of essential oil pared using a similar methods reported in the references molecules can be based on retaining their activity, the [21, 22]. application of plant essential oils will undoubtedly be a significant development. Recently, during the course of our research for functional molecules based on natural General synthetic procedures for target compounds essential oils [19, 20], a series of essential oil-oriented The corresponding acid bearing 1,3-benzodioxole derivatives have been synthesized and approved to unit (0.005  mol), phenolic compound (0.005  mol) and exhibit insecticidal or fungicidal activities, which suggest acetonitrile (30–60  mL) were added to a 150  mL dry that these natural essential oils might contribute to the round bottom flask, and 0.3  g of 4-dimethylamino - biological functions. pyridine was added as a catalyst, and 1.5  g of N,N′- Based on this investigation, a series of piperine-ori- dicyclohexylcarbodiimide was further added as a ented derivatives derived from natural phenolic com- condensing agent. The reaction was stirred at room tem - pounds existed in essential oils were designed and perature to 40  °C for additional hours, and TLC traced synthesized as following strategy in Fig. 1. So, in order to the reaction to completion. After the completion of the explore the potential applications for these novel essential reaction, the solution was dissolved in water (20  mL), oil derivatives, we report herein the synthesis and charac- and the aqueous solution was extracted with ethyl acetate terization of twenty-one essential oil derivatives via sim- (30  mL × 2) twice. The combined organic phases were ple reaction, and their antifungal activities against several washed with 5% N a CO solution (30 mL × 2) and water 2 3 phytopathogenic fungi have also been fully investigated. to neutrality and dried over anhydrous Na SO . After fil - 2 4 tration and concentration, the corresponding crude com- Materials and methods pound were obtained, which were purified by silica gel Instrumentation and chemicals column-chromatography (ethyl acetate/petroleum ether) All chemicals or reagents used for syntheses were of or recrystallization to give pure compounds. analytical reagent, and used directly without purifica - tion. Melting points (m.p.) were determined on a RY-2 apparatus and are uncorrected. H NMR spectra were 5‑Isopropyl‑2‑methylphenyl benzo[d][1,3] recorded on a Brucker spectrometer at 600  MHz with dioxole‑5‑carboxylate (1a) the CDCl as the solvent and TMS as the internal stand- H NMR (600 MHz, C DCl ): δ = 7.85 (dd, J = 8.2, 1.8  Hz, 3 3 ard. C NMR spectra were recorded on a Brucker spec- 1H), 7.64 (d, J = 1.8 Hz, 1H), 7.19 (d, J = 7.8 Hz, 1H), 7.05 trometer at 150  MHz with CDCl as the solvent. Mass (dd, J = 7.8, 1.8 Hz, 1H), 6.98 (d, J = 1.8 Hz, 1H), 6.92 (d, spectra were performed on a Waters ACQUITY U PLC J = 8.2  Hz, 1H), 6.08 (s, 2H), 2.93–2.88 (m, 1H), 2.18 (s, ® 13 H-CLASS PDA (Waters ) instrument. Column chroma- 3H), 1.25 (d, J = 6.6 Hz, 6H); C NMR (150 MHz, CDCl ): tography was carried out using silica gel 100–200  mesh. δ = 164.39, 152.25, 149.59, 148.23, 148.04, 131.03, 127.51, Analytical thin-layer chromatography (TLC) was carried 126.26, 124.26, 123.63, 120.04, 110.08, 108.31, 102.08, out on precoated plates, and spots were visualized with 33.74, 24.07, 15.98; MS (ESI) m/z 299.6 (M+H) , calcd. ultraviolet light.for C H O m/z = 299.1. 18 19 4 Fig. 1 Design strategy of piperine-based essential oils derivatives W ang et al. BMC Chemistry (2020) 14:24 Page 3 of 12 2‑Isopropyl‑5‑methylphenyl benzo[d][1,3] 152.39, 151.72, 147.98, 132.37, 126.49, 111.97, 110.07, dioxole‑5‑carboxylate (1b) 109.25, 108.30, 102.01, 55.75, 29.52; MS (ESI) m/z 337.4 1 + H NMR (600 MHz, C DCl ): δ = 7.84–7.82 (m, 1H), 7.62 (M+Na) , calcd. for C H NaO m/z = 337.1. 3 17 14 6 (s, 1H), 7.26–7.20 (m, 1H), 7.05 (d, J = 7.4 Hz, 1H), 6.94– 6.88 (m, 3H), 6.06 (s, 2H), 3.06–3.01 (m, 1H), 2.33 (s, 3H), 2‑(Methoxycarbonyl)phenyl benzo[d][1,3] 1.20 (d, J = 7.2  Hz, 6H); C NMR (150  MHz, C DCl ): dioxole‑5‑carboxylate (1g) δ = 164.72, 152.15, 148.15, 147.93, 137.17, 136.60, 127.10, H NMR (600 MHz, C DCl ): δ = 8.06 (dd, J = 7.8, 1.8  Hz, 126.43, 126.12, 123.51, 122.90, 109.91, 108.20, 101.96, 1H), 7.85 (dd, J = 8.2, 1.8 Hz, 1H), 7.64 (d, J = 1.6 Hz, 1H), 27.29, 22.67, 20.85; MS (ESI) m/z 299.5 (M+H) , calcd. 7.61–7.59 (m, 1H), 7.36–7.34 (m, 1H), 7.22 (dd, J = 8.1, for C H O m/z = 299.1. 18 19 4 0.8 Hz, 1H), 6.92 (d, J = 8.2 Hz, 1H), 6.08 (s, 2H), 3.76 (s, 3H); C NMR (150  MHz, CDCl ): δ = 165.04, 164.68, Benzo[d][1,3]dioxol‑5‑yl benzo[d][1,3]dioxole‑5‑carboxylate 152.19, 150.83, 147.89, 133.80, 131.87, 126.36, 126.00, (1c) 124.00, 123.48, 123.40, 110.07, 108.22, 101.94, 52.21; H NMR (600 MHz, CDCl ): δ = 7.80 (dd, J = 8.2, 1.8  Hz, MS (ESI) m/z 323.4 (M+Na) , calcd. for C H NaO 16 12 6 1H), 7.59 (d, J = 1.8  Hz, 1H), 6.90 (d, J = 8.2  Hz, 1H), m/z = 323.1. 6.81 (d, J = 8.4 Hz, 1H), 6.71 (d, J = 2.4 Hz, 1H), 6.63 (dd, J = 8.4, 2.4  Hz, 1H), 6.08 (s, 2H), 6.00 (s, 2H); C NMR 5‑Isopropyl‑2‑methylphenyl 3‑(benzo[d][1,3]dioxol‑5‑yl) (150 MHz, CDCl ): δ = 164.82, 152.20, 147.90, 145.36, acrylate (2a) 126.19, 123.30, 114.06, 109.92, 108.15, 108.01, 103.92, + H NMR (600  MHz, C DCl ): δ = 7.79 (d, J = 16.2  Hz, 101.97, 101.71; MS (ESI) m/z 287.5 (M+H) , calcd. for 3 1H), 7.17 (d, J = 7.8  Hz, 1H), 7.11–7.02 (m, 3H), 6.93 C H O m/z = 287.0. 15 11 6 (s, 1H), 6.03 (s, 2H), 6.84 (d, J = 8.0  Hz, 1H), 6.48 (d, J = 15.6 Hz, 2H), 6.03 (s, 2H), 2.91–2.87 (m, 1H), 1.24 (d, 4‑Allyl‑2‑methoxyphenyl benzo[d][1,3]dioxole‑5‑carboxylate J = 7.2  Hz, 6H); C NMR (150 MHz, C DCl ): δ = 165.41, (1d) 149.94, 149.33, 148.03, 146.11, 128.66, 127.37, 124.85, H NMR (600  MHz, CDCl ): δ = 7.83 (dd, J = 8.2, 124.08, 119.84, 115.08, 106.60, 101.65, 33.58, 23.92, 1.8 Hz, 1H), 7.62 (d, J = 1.8 Hz, 1H), 7.26 (s, 1H), 7.04 (d, 15.86; MS (ESI) m/z 325.6 (M+H) , calcd. for C H O 20 21 4 J = 8.0 Hz, 1H), 6.89 (d, J = 8.2 Hz, 1H), 6.82 (d, J = 1.8 Hz, m/z = 325.1. 1H), 6.06 (s, 2H), 6.00–5.95 (m, 1H), 5.16–5.06 (m, 2H), 3.80 (s, 3H), 3.40 (d, J = 7.2 Hz, 2H); C NMR (150 MHz, 2‑Isopropyl‑5‑methylphenyl 3‑(benzo[d][1,3]dioxol‑5‑yl) CDCl ): δ = 164.24, 152.02, 151.10, 147.80, 138.96, acrylate (2b) 138.21, 137.11, 126.27, 123.40, 122.66, 120.71, 116.12, H NMR (600  MHz, CDCl ): δ = 7.78 (d, J = 16.2  Hz, 112.83, 110.12, 108.09, 101.88, 55.89, 40.12; MS (ESI) m/z 1H), 7.22 (d, J = 7.8  Hz, 1H), 7.13–7.01 (m, 4H), 6.87 (d, 335.6 (M+Na) , calcd. for C H NaO m/z = 335.1. 18 16 5 d, J = 7.8  Hz, 1H), 6.48 (d, J = 15.6  Hz, 1H), 6.03 (s, 2H), 3.05–3.01 (m, 1H), 2.33 (s, 3H) 1.21 (d, J = 7.2  Hz, 6H); 2,6‑Dimethoxyphenyl benzo[d][1,3]dioxole‑5‑carboxylate C NMR (150 MHz, C DCl ): δ = 165.88, 149.95, 148.45, (1e) 147.99, 146.12, 137.21, 136.55, 128.65, 127.07, 124.87, H NMR (600 MHz, C DCl ): δ = 7.86 (dd, J = 8.2, 1.8  Hz, 122.81, 115.16, 108.63, 106.63, 101.65, 27.16, 23.08, 1H), 7.66 (d, J = 1.8  Hz, 1H), 7.17–7.16 (m, 1H), 6.89 20.86; MS (ESI) m/z 325.5 (M+H) , calcd. for C H O 20 21 4 (d, J = 8.2  Hz, 1H), 6.64 (d, J = 8.4  Hz, 1H), 6.06 (s, 2H), m/z = 325.1. 13 1 3.80 (s, 6H); C NMR H NMR (150  MHz, CDCl ): δ = 163.88, 152.57, 151.98, 147.76, 128.95, 126.41, 126.23, 123.32, 110.29, 108.07, 104.95, 101.85, 56.19; MS (ESI) Benzo[d][1,3]dioxol‑5‑yl 3‑(benzo[d][1,3]dioxol‑5‑yl)acrylate m/z 325.5 (M+Na) , calcd. for C H NaO m/z = 325.1. (2c) 16 14 6 H NMR (600  MHz, C DCl ): δ = 7.68 (d, J = 15.6  Hz, 1H), 7.04–6.97 (m, 2H), 6.77 (d, J = 8.0  Hz, 1H), 6.73 (d, 2‑Acetyl‑5‑methoxyphenyl benzo[d][1,3] J = 8.4  Hz, 1H), 6.61 (d, J = 2.4  Hz, 1H), 6.53 (dd, J = 8.4, dioxole‑5‑carboxylate (1f ) 2.4  Hz, 1H), 5.96 (s, 2H), 5.92 (s, 2H). 5.84 (s, 1H); C H NMR (600 MHz, CDCl ): δ = 7.89 (d, J = 8.8  Hz, 1H), NMR (150  MHz, C DCl ): δ = 165.90, 150.02, 148.46, 7.84 (dd, J = 8.2, 1.8 Hz, 1H), 7.62 (d, J = 1.8 Hz, 1H), 6.92 148.00, 146.33, 145.29, 145.15, 128.60, 124.93, 114.97, (d, J = 8.2 Hz, 1H), 6.87 (dd, J = 8.8, 2.4 Hz, 1H), 6.70 (d, 114.01, 108.65, 108.00, 106.60, 103.86, 101.69, 101.18; J = 2.4  Hz, 1H), 6.08 (s, 3H), 3.87 (s, 3H), 2.49 (s, 3H); MS (ESI) m/z 313.5 (M+H) , calcd. for C H O 17 13 6 C NMR (150 MHz, CDCl ): δ = 195.68, 164.42, 163.73, m/z = 313.1. Wang et al. BMC Chemistry (2020) 14:24 Page 4 of 12 4‑Allyl‑2‑methoxyphenyl 3‑(benzo[d][1,3]dioxol‑5‑yl)acrylate 1H), 5.93 (s, 2H), 2.83–2.79 (m, 1H), 2.08 (s, 3H), 1.16 (d, (2d) J = 14.6 Hz, 6H); C NMR (150 MHz, CDCl ): δ = 165.51, H NMR (600 MHz, CDCl ): δ = 7.70 (d, J = 15.6 Hz, 1H), 149.31, 148.79, 148.35, 148.04, 146.69, 141.25, 130.88, 7.05–6.92 (m, 3H), 6.79–6.69 (m, 3H), 6.42 (d, J = 15.9 Hz, 130.40, 127.42, 124.33, 124.11, 123.34, 119.88, 119.20, 1H), 5.98–5.85 (m, 3H), 5.09–5.00 (m, 2H), 3.76 (s, 3H), 108.63, 105.93, 101.50, 33.61, 24.08, 15.92; MS (ESI) m/z 3.33 (d, J = 6.7  Hz, 2H); C NMR (150  MHz, C DCl ): 373.5 (M+Na) , calcd. for C H NaO m/z = 373.2. 3 22 22 4 δ = 165.32, 151.04, 149.87, 148.41, 146.15, 138.92, 138.03, 137.10, 128.76, 124.83, 122.67, 120.71, 116.15, 114.97, 2‑Isopropyl‑5‑methylphenyl 5‑(benzo[d][1,3]dioxol‑5‑yl) 112.76, 108.61, 106.65, 101.62, 55.90, 40.14; MS (ESI) m/z penta‑2,4‑dienoate (3b) 361.6 (M+Na) , calcd. for C H NaO m/z = 361.1. H NMR (600 MHz, C DCl ): δ = 7.55–7.51 (m, 1H), 7.15 20 18 5 3 (d, J = 7.8  Hz, 1H), 6.96–6.95 (m, 2H), 6.87–6.86 (m, 2,6‑Dimethoxyphenyl 3‑(benzo[d][1,3]dioxol‑5‑yl)acrylate 2H), 6.79 (s, 1H), 6.74–6.71 (m, 2H), 6.09 (d, J = 15.0  Hz, (2e) 1H), 5.92 (s, 2H), 2.96–2.91 (m, 1H), 2.24 (s, 3H), 1.12 (d, H NMR (600  MHz, C DCl ): δ = 7.72 (d, J = 15.6  Hz, J = 6.6  Hz, 6H); C NMR (150 MHz, C DCl ): δ = 166.02, 3 3 1H), 7.10–7.07 (m, 1H), 7.03 (d, J = 1.8  Hz, 1H), 7.00 148.81, 148.36, 147.97, 146.71, 141.32, 137.22, 136.60, (d, J = 7.5  Hz, 1H), 6.76 (d, J = 7.8  Hz, 1H), 6.57 (d, 130.40, 127.11, 126.46, 124.33, 123.36, 122.87, 119.27, J = 9.0 Hz, 2H), 6.48 (d, J = 16.2 Hz, 1H), 5.96 (s, 2H), 3.76 108.64, 105.93, 101.52, 27.17, 22.75, 20.94; MS (ESI) m/z (s, 6H); C NMR (150 MHz, CDCl ): δ = 164.89, 152.51, 373.5 (M+Na) , calcd. for C H NaO m/z = 373.2. 3 22 22 4 149.82, 148.37, 146.23, 128.85, 126.22, 124.83, 114.83, 108.59, 106.69, 104.92, 101.60, 56.21; MS (ESI) m/z 351.5 Benzo[d][1,3]dioxol‑5‑yl 5‑(benzo[d][1,3]dioxol‑5‑yl) (M+Na) , calcd. for C H NaO m/z = 351.1. penta‑2,4‑dienoate (3c) 18 16 6 H NMR (600  MHz, C DCl ): δ = 7.57 (dd, J = 15.2, 2‑Acetyl‑5‑methoxyphenyl 3‑(benzo[d][1,3]dioxol‑5‑yl) 11.0  Hz, 1H), 7.02 (d, J = 1.6  Hz, 1H), 6.94 (dd, J = 8.0, acrylate (2f ) 1.6 Hz, 1H), 6.88 (d, J = 15.0 Hz, 1H), 6.81–6.77 (m, 3H), H NMR (600 MHz, CDCl ): δ = 7.89 (d, J = 9.0  Hz, 1H), 6.66 (d, J = 2.4 Hz, 1H), 6.58 (dd, J = 8.4, 2.4 Hz, 1H), 6.09 7.82 (d, J = 15.6  Hz, 1H), 7.13 (d, J = 1.6  Hz, 1H), 7.11– (d, J = 15.2  Hz, 1H), 5.99 (d, J = 9.6  Hz, 4H); C NMR 7.09 (m, 1H), 6.87 (dd, J = 8.6, 2.4  Hz, 2H), 6.70 (s, 1H), (150 MHz, CDCl ): δ = 165.84, 148.81, 148.34, 147.95, 6.52 (d, J = 15.6  Hz, 1H), 6.06 (s, 2H), 3.88 (s, 3H), 2.54 146.76, 145.23, 145.15, 141.34, 130.37, 124.27, 123.27, (s, 3H); C NMR (150 MHz, CDCl ): δ = 195.96, 165.36, 119.07, 113.99, 108.59, 107.96, 105.95, 103.86, 101.65, 163.69, 151.51, 150.14, 148.45, 147.07, 132.26, 128.51, 101.45; MS (ESI) m/z 339.2 (M+H) , calcd. for C H O 19 15 6 125.18, 123.68, 114.68, 111.89, 109.12, 108.64, 106.71, m/z = 339.1. 101.69, 55.74, 29.61; MS (ESI) m/z 363.5 (M+Na) , calcd. for C H NaO m/z = 363.1. 4‑Allyl‑2‑methoxyphenyl 5‑(benzo[d][1,3]dioxol‑5‑yl) 19 16 6 penta‑2,4‑dienoate (3d) Methyl 2‑((3‑(benzo[d][1,3]dioxol‑5‑yl)acryloyl)oxy)benzoate H NMR (600  MHz, C DCl ): δ = 7.64–7.60 (m, 1H), (2g) 7.16–7.13 (m, 1H), 7.03 (d, J = 1.8  Hz, 1H), 6.94 (dd, H NMR (600 MHz, CDCl ): δ = 7.97 (d, J = 9.0  Hz, 1H), J = 8.0, 1.8  Hz, 1H), 6.87 (d, J = 15.6  Hz, 1H), 6.81–6.78 7.73 (d, J = 15.6  Hz, 1H), 7.53–7.50 (m, 1H), 7.27 (d, (m, 2H), 6.63 (d, J = 8.4 Hz, 2H), 6.22 (d, J = 15.2 Hz, 1H), J = 8.0 Hz, 1H), 7.19 (s, 2H), 7.11 (d, J = 7.8 Hz, 1H), 7.04– 6.00 (s, 2H), 3.82 (s, 6H); C NMR (150  MHz, C DCl ): 7.00 (m, 2H), 6.77 (d, J = 8.0 Hz, 1H), 6.45 (d, J = 15.6 Hz, δ =164.83, 152.51, 148.68, 148.31, 146.65, 140.92, 130.53, 1H), 5.96 (s, 2H), 3.77 (s, 3H); C NMR (150  MHz, 128.80, 126.14, 124.54, 123.14, 119.03, 108.55, 105.96, CDCl ): δ = 165.61, 165.14, 150.65, 149.99, 148.43, 104.92, 101.42, 56.19; MS (ESI) m/z 365.4 (M+H) , calcd. 146.55, 133.79, 131.77, 128.67, 125.94, 125.01, 123.91, for C H O m/z = 365.1. 22 21 5 123.56, 114.87, 108.61, 106.70, 101.66, 52.25; MS (ESI) m/z 349.4 (M+Na) , calcd. for C H NaO m/z = 349.1. 2,6‑Dimethoxyphenyl 5‑(benzo[d][1,3]dioxol‑5‑yl) 18 14 6 penta‑2,4‑dienoate (3e) 5‑Isopropyl‑2‑methylphenyl 5‑(benzo[d][1,3]dioxol‑5‑yl) H NMR (600  MHz, C DCl ): δ = 7.64–7.60 (m, 1H), penta‑2,4‑dienoate (3a) 7.16–7.13 (m, 1H), 7.03 (d, J = 1.8  Hz, 1H), 6.94 (dd, H NMR (600  MHz, C DCl ): δ = 7.83–7.79 (m, J = 15.2, J = 8.0, 1.8  Hz, 1H), 6.87 (d, J = 15.6  Hz, 1H), 6.81–6.78 10.9 Hz, 1H), 7.09 (d, J = 7.8 Hz, 1H), 6.96–6.95 (m, 3H), (m, 2H), 6.63 (d, J = 8.4 Hz, 2H), 6.22 (d, J = 15.2 Hz, 1H), 6.88–6.80 (m, 3H), 6.75–6.70 (m, 2H), 6.09 (d, J = 15.2 Hz, 6.00 (s, 2H), 3.82 (s, 6H); C NMR (150  MHz, C DCl ): 3 W ang et al. BMC Chemistry (2020) 14:24 Page 5 of 12 107.55, 104.93, 100.43, 51.20; MS (ESI) m/z 375.5 δ = 164.83, 152.51, 148.68, 148.31, 146.65, 140.92, 130.53, (M+Na) , calcd. for C H NaO m/z = 375.1. 128.80, 126.14, 124.54, 123.14, 119.03, 108.55, 105.96, 20 16 6 104.92, 101.42, 56.19; MS (ESI) m/z 377.4 (M+Na) , Biological assay calcd. for C H NaO m/z = 377.1. 20 18 6 The in vitro fungicidal activities of the target compounds 1a–3g against Rhizoctonia solani, Fusarium gramine- 2‑Acetyl‑5‑methoxyphenyl 5‑(benzo[d][1,3]dioxol‑5‑yl) arum, Phomopsis adianticola, Alternaria tenuis Nees, penta‑2,4‑dienoate (3f ) Phytophthora capsici and Gloeosporium theae-sinensis H NMR (600 MHz, CDCl ): δ = 7.86 (d, J = 8.8  Hz, 1H), were evaluated using mycelium growth rate test, and all 7.63 (dd, J = 15.2, 11.0  Hz, 1H), 7.03 (d, J = 1.6  Hz, 1H), the procedure for bioassay were according to the meth- 6.98–6.87 (m, 3H), 6.86–6.78 (m, 4H), 6.66 (d, J = 2.5  Hz, ods reported in literature [23]. 1H), 6.18 (d, J = 15.2  Hz, 1H), 6.00 (s, 2H), 3.85 (s, 3H), 2.51 (s, 3H); C NMR (150  MHz, CDCl ): δ = 192.87, Results and discussion 165.23, 163.65, 151.54, 148.89, 148.36, 147.49, 141.78, Synthesis 132.19, 130.34, 124.26, 123.71, 117.79, 111.86, 109.06, A series of novel compounds 1a–g, 2a–g and 3a–g 108.60, 105.98, 101.47, 55.71, 29.69; MS (ESI) m/z 389.4 derived from natural phenolic compounds existed in (M+Na) , calcd. for C H NaO m/z = 389.1. 21 18 6 essential oils based on piperine scaffold can be syn - thesized by a mild and simple method as described in Methyl 2‑((5‑(benzo[d][1,3]dioxol‑5‑yl)penta‑2,4‑dienoyl) Scheme 1. In brief, the intermediate (E)-3-(benzo[d][1,3] oxy)benzoate (3g) dioxol-5-yl)acrylic acid (n = 1) can be prepared using H NMR (600 MHz, C DCl ): δ = 7.95 (dd, J = 7.8, 1.8  Hz, piperonal as starting materials [21], and the other inter- 1H), 7.59–7.46 (m, 2H), 7.27–7.21 (m, 1H), 7.08 (dd, mediate piperic acid (n = 2) was synthesized via basic J = 8.2, 0.8  Hz, 1H), 6.95 (d, J = 1.6  Hz, 1H), 6.87 (dd, hydrolysis reaction of piperine [22]. Then, all three acids J = 8.0, 1.6  Hz, 1H), 6.81 (d, J = 15.6  Hz, 1H), 6.76–6.68 were coupling with various essential oils molecules to (m, 2H), 6.12 (d, J = 15.2  Hz, 1H), 5.92 (s, 4H), 3.76 (s, obtain the corresponding esters using an optimization 2H); C NMR (150  MHz, CDCl ): δ = 164.51, 164.12, method. 149.61, 147.76, 147.31, 145.94, 140.29, 132.71, 130.70, 129.39, 124.85, 123.40, 122.89, 122.53, 122.22, 118.00, Scheme 1 Synthetic route for intermediates and target molecules Wang et al. BMC Chemistry (2020) 14:24 Page 6 of 12 Table 1 The optimal reaction conditions of  piperic acid Table 2, and their chemical structures and basic physico- and carvacrol chemical properties were summarized in “Materials and methods”. Entry Catalytic Solvent Temperature Time (h) Yield (%) system (°C) Spectrum analyses 1 DCC/DMAP THF 40 6 47.47 The structures of all target compounds 1a– 3g were con- 2 DCC/DMAP DCM 40 6 78.42 1 13 firmed by H NMR, C NMR (Additional file  1) and 3 DCC/DMAP MeCN 40 6 83.40 mass spectrometry, and their structures were well con- 4 DCC/DMAP MeCN 60 6 68.55 sistent with all the spectral data. A representative H 5 DCC/DMAP MeCN 90 6 65.46 NMR spectrum of 1c is shown in Fig. 2, and each hydro- 6 EDCI/HOBT MeCN 40 6 NR gen shows a characteristic absorption peak. The methyl - 7 CDI/DIPEA MeCN 40 6 NR ene group on the piperine skeleton was not affected by other H in the ortho position, and a single peak appeared at 6.06  ppm, and the H of the benzene ring showed between 7.81 and 6.62 ppm. To achieve the above goal for these essential oil deriva- tives, the initial experiment was optimized, and the dif- Biological activity ferent reaction conditions have been explored (Table  1). Primary screening test As can be seen from Table  1 (Entry 6 and 7), when the In this study, all essential oil derivatives 1a–g, 2a–g, and condensation system is EDCI/HOBT or CDI/DIPEA, 3a–g were screened for their antifungal activities in vitro TLC analysis showed that no obvious product was pro- against six common plant pathogenic fungi (Rhizocto- duced, however, the yields are improved when the con- nia solani, Fusarium graminearum, Alternaria tenuis densation reactions are performed under the DCC/ Nees, Gloeosporium theae-sinensis, Phytophthora capsici, DMAP system. With this condition (DCC/DMAP) Phomopsis adianticola), and the preliminary screening in hand, the solvent is further screened, and an equal results were outlined in Table 3. volume of acetonitrile, tetrahydrofuran and dichlo- Generally, as shown in Table  3, the preliminary assay romethane are used as solvents. The reaction time and illustrated that some compounds of the essential oil temperature are the same. The relationship between sol - derivatives based on piperine displayed good inhibi- vent and yield was obtained, as shown in Table  1, when tory activities against some tested fungal strains, and acetonitrile was the solvent, the yield was the highest. In we also can find that some of the target compounds order to investigate the effect of the target compound have better inhibitory activities than piperine and car- yield on the reaction temperature, the experiment was bendazim at the concentration of 100  µg/mL. Nota- carried out at a reaction temperature of 40  °C, 60  °C, bly, six compounds displayed fungicidal activity more and 90  °C, respectively. The results show that the yield than 40% against Rhizoctonia solani, especially com- gradually decreases with increasing temperature, and pound 1f displayed an 65.00% inhibition rate, better the yield is highest at 40  °C. Finally, we determined the than that of piperine (63.13%). Three compounds dis - optimal synthetic conditions for the synthesis of pepper played fungicidal activity more than 40% against Fusar- acid-directed essential oil derivatives: DCC/DMAP is a ium graminearum, except compound 2b displayed catalytic condensation system, the solvent is acetonitrile, an 62.61% inhibition rate, better than that of piperine the reaction temperature is 40  °C, and the yield of the (53.04%). Four compounds displayed fungicidal activity target compound is 83.40%. more than 40% against Alternaria tenuis Nees, except All of the new natural phenolic derivatives were syn- compound 1d displayed 71.07% inhibition rate, better thesized according to the optimal conditions described than that of the piperine (66.12%) and carbendazim above, and the structures of all the obtained compounds (13.22%). Five compounds displayed fungicidal activ- in this study were confirmed by satisfactory spectral ity more than 40% against Gloeosporium theae-sinensis, 1 13 analysis, including H NMR, C NMR, ESI–MS. The 2b displayed an 66.92% inhibition rate, which is less chemical formulas of all compounds were described in than the activity of piperine (76.92%). Four compounds W ang et al. BMC Chemistry (2020) 14:24 Page 7 of 12 Table 2 The chemical structure of target compounds 1a–3g Compd. no.Structure Appearance MP (°C) Yield (%) Yellowish 1a –83.4 liquid 1b White solid 61–6366.0 1c White solid 117–120 42.3 1d Yellowishsolid 68–7278.85 1e White solid 158–160 57.7 1f White solid 116–120 88.46 1g White solid 93–9683.90 Brownish 2a yellow 45–4981.20 semisolid 2b White solid 70–7375.6 2c White solid 134–137 80.3 2d White solid 121–125 77.8 2e White solid 174–178 85.6 2f White solid 137–141 77.8 Wang et al. BMC Chemistry (2020) 14:24 Page 8 of 12 Table 2 (continued) Compd. no.Structure Appearance MP (°C) Yield (%) 2g White solid 122–12584.6 Yellow 3a 68–7255.8 semisolid 3b Yellowish solid 89–9173.5 3c Yellowish solid 136–138 59.3 3d Yellowish solid 109–113 62.13 Orange-yellow 3e 155–158 53.8 solid Orange-yellow 3f 127–130 53.0 solid 3g Yellow solid 115–118 40.06 displayed fungicidal activity more than 40% against activities, we thus selected some compounds like 1a, Phytophthora capsici, except compound 2b displayed 1b, 1c, 1d, 1g, 2a, 2b, 2g to have further exploration an 100% inhibition rate, which is much greater than in such a situation, and compared the values of IC the piperine (41.88%) and carbendazim (34.27%). Four with piperine and carbendazim at different concentra - compounds displayed fungicidal activity more than tions. The fungicidal activities expressed as IC values 40% against Phomopsis adianticola, except compound for highly potential compounds are listed in Table  4, 2b displayed an 100% inhibition rate, far superior to the which indicated some compounds had good inhibi- piperine (29.63%). tory effects. As shown in Table  4, compounds 1a, 1g, 2b, 2g (IC = 11.21, 87.66, 7.79, 97.84  μg/mL) all dis- played good inhibitory effects on Phytophthora cap - Secondary screening test sici compared with the positive control carbendazim The preliminary assay indicated many of the target (IC > 100  μg/mL). Compounds 1a and 2b displayed compounds exhibited good fungicidal activities com- good inhibitory effects compared with the piperine pared to the commercial fungicide carbendazim, in (IC = 34.87 μg/mL). In particular, 2b exhibits a broad order to further investigate the potential fungicidal spectrum of bacteriostatic activity. W ang et al. BMC Chemistry (2020) 14:24 Page 9 of 12 Fig. 2 Representative H NMR spectra for compound 1c 1 13 In addition, the Fig.  3 indicated the inhibition effects were characterized by H-NMR, C-NMR and ESI– of target compounds 1a, 2b on Phomopsis adianticola MS spectra analyses, and potential bioactivity was also compared with that of piperine and carbendazim, which assessed. Preliminary bioassay results indicate that some confirmed that the compounds 1a and 2b displayed new compounds show better fungistatic activity than pip- the superior fungicidal activities on the Phomopsis adi- erine. Among them, compound 2b exhibits a broad spec- anticola at different concentrations of 12.5, 25, 50, 100, trum of fungicidal activity, and it is hoped that further 200 µg/mL. development of a new piperine-oriented agrochemicals. Conclusions In summary, 21 piperine-directed essential oil derivatives have been designed, synthesized and evaluated as poten- tial fungicides. The structures of all obtained molecules Wang et al. BMC Chemistry (2020) 14:24 Page 10 of 12 Table 3 In vitro fungicidal activity of target compounds 1a–3g Entry Compd. no. In vitro fungicidal activity (%)/100 µg/mL a a a a a a R.S F.G A.T G.T P.C P.A 1 1a 21.88 18.26 47.11 51.54 68.38 68.89 2 1b 29.69 36.52 52.89 35.77 31.62 61.85 3 1c 57.50 0.00 −1.65 4.62 14.53 3.70 4 1d 30.63 17.39 71.07 52.31 24.79 40.00 5 1e 17.50 15.65 25.62 27.69 29.06 3.70 6 1f 65.00 31.74 33.06 26.92 30.77 47.41 7 1g 20.94 22.61 7.44 0.00 47.86 23.70 8 2a 18.13 34.78 34.71 43.08 35.90 45.19 9 2b 57.50 62.61 52.07 66.92 100 100.00 10 2c 35.94 18.26 7.44 15.38 35.90 −3.70 11 2d 37.19 19.13 7.44 18.08 38.46 0.00 12 2e 63.75 21.74 −3.31 3.08 27.35 3.70 13 2f 40.94 20.87 2.48 13.85 33.33 −2.22 14 2g 46.56 11.30 9.92 60.77 47.01 29.63 15 3a 30.94 46.09 23.97 30.77 33.33 18.52 16 3b 25.00 35.65 25.62 15.38 23.08 16.30 17 3c 20.94 35.65 13.22 15.00 5.98 3.70 18 3d 21.25 45.22 24.79 38.46 19.66 17.04 19 3e 15.63 33.04 16.53 24.62 24.79 18.52 20 3f 7.81 37.09 16.53 23.08 0.85 29.63 21 3g 18.13 24.35 17.36 30.77 15.38 29.63 22 Piperine 63.13 53.04 66.12 76.92 41.88 29.63 23 Carbendazim 100.00 100.00 13.22 100.00 34.27 100.00 R.S, Rhizoctonia solani; F.G - Fusarium graminearum, A.T, Alternaria tenuis Nees; G.T, Gloeosporium theae-sinensis; P.C, Phytophthora capsici; P.A, Phomopsis adianticola Table 4 The IC of some compounds against the plant pathogen fungi Entry Compd. no. IC (µg/mL) R.S F.G A.T G.T P.C P.A 1 1a 39.92 156.99 43.06 64.65 11.21 35.67 2 1b 29.29 > 200 121.77 >200 – 45.75 3 1c 69.06 – – – – – 4 1d – – – 142.36 – – 5 1g – – – – 87.66 – 6 2a 89.50 – – – – 72.66 7 2b 39.46 38.83 12.02 22.55 7.79 8.84 8 2g – – >200 81.95 97.54 – 9 Piperine 89.50 >200 116.77 42.84 34.87 84.88 10 Carbendazim 2.94 3.30 173.18 2.86 114.42 3.73 IC —compound concentration required to inhibit colony growth by 50% R.S, Rhizoctonia solani; F.G, Fusarium graminearum; A.T, Alternaria tenuis Nees; G.T, Gloeosporium theae-sinensis; P.C, Phytophthora capsici; P.A, Phomopsis adianticola Carbendazim, used as positive control W ang et al. BMC Chemistry (2020) 14:24 Page 11 of 12 Fig. 3 Inhibition activity of compounds 1a, 2b, piperine and carbendazim on Phomopsis adianticola. a–e The concentration of compounds 1a, 2b, piperine and carbendazim are 12.5, 25, 50, 100, and 200 µg/mL; CK blank control Competing interests Supplementary information The authors declare no conflicts of interest. Supplementary information accompanies this paper at https ://doi. org/10.1186/s1306 5-020-00676 -4. Received: 15 November 2019 Accepted: 16 March 2020 1 13 Additional file 1. H NMR, and C NMR spectra for the target compounds. References 1. Mujumdar AM, Dhuley JN, Deshmukh VK, Raman PH, Thorat SL, Naik SR Abbreviations (1990) Eec ff t of piperine on pentobarbitone induced hypnosis in rats. EOs: Essential oils; m.p.: Melting points; TLC: Analytical thin-layer chromatog- Indian J Exp Biol 28:486–487 raphy; R.S: Rhizoctonia solani; F.G: Fusarium graminearum; A.T: Alternaria tenuis 2. 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Mann RS, Tiwari S, Smoot JM, Rouseff RL, Stelinski LL (2012) Repellency Springer Nature remains neutral with regard to jurisdictional claims in pub- and toxicity of plant-based essential oils and their constituents against lished maps and institutional affiliations. Diaphorina citri Kuwayama (Hemiptera: Psyllidae). J Appl Entomol 136:87–96 Ready to submit your research ? Choose BMC and benefit from: fast, convenient online submission thorough peer review by experienced researchers in your field rapid publication on acceptance support for research data, including large and complex data types • gold Open Access which fosters wider collaboration and increased citations maximum visibility for your research: over 100M website views per year At BMC, research is always in progress. Learn more biomedcentral.com/submissions http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Chemistry Central Journal Springer Journals

Natural phenolic derivatives based on piperine scaffold as potential antifungal agents

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Copyright © The Author(s) 2020
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10.1186/s13065-020-00676-4
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Abstract

Piperine is a natural alkaloid with a wide range of biological functions. Natural phenolic compounds existed in many essential oils (EOs) are plant-derived aroma compounds with broad range of biological activities, however, their actions are slow, and they are typically unstable to light or heat, difficult to extract and so on. In order to find high- potential fungicides derived from piperine, a series of piperine-directed essential oil derivatives were designed and 1 13 synthesized. The structures of all molecules were confirmed by satisfied spectral data, including H NMR, C NMR and ESIMS. The target compounds were screened for their potential fungicidal activities against six species of plant patho- gen fungi, including Rhizoctonia solani, Fusarium graminearum, Phomopsis adianticola, Alternaria tenuis Nees, Phytoph- thora capsici and Gloeosporium theae-sinensis. Some of target compounds exhibited moderate and broad-spectrum activity against tested fungi compared to the parental piperine. Further studies have shown that some different concentrations of compounds have significant inhibitory activity against Alternaria tenuis Nees and Phytophthora capsici compared to commercial carbendazim, and compound 2b exhibited particularly significant broad-spectrum fungicidal activity. Keywords: Piperine, Essential oils, Synthesis, Fungicidal activity Introduction and intermediate [11]. Its structure is mainly divided into Piperine, a natural amide compound, is the main active three parts: piperidine ring, aromatic heterocyclic ring, substance extracted of Piper nigrum Linn. As an impor- and aliphatic hydrocarbon chain. These three places are tant natural alkaloid, piperine exhibited a wide spectrum usually considered by the researchers to be essential for of biological and pharmacological activities [1–6], it has their biological activity, and by modifying the structure of anti-oxidation, antidepressant [7], toxic effect against these parts, the biological activity of the compounds can be changed. hepatocytes [8], antiapoptotic efficacy [9], high immu - Essential oils (EOs) are class of complex mixtures of nomodulatory and antitumor activity [4], and has obvi- low molecular weight compounds extracted from vari ous effects in lowering blood fat [10]. Clinically, it can - effectively control the incidence of hyperlipidemia, the ous plants by steam distillation and various solvents [12]. treatment rate is as high as 93.3%, and it can also reduce Plant essential oils have received extensive attention from the incidence of cardiovascular and cerebrovascular dis- plant protection experts in recent years due to their low eases. In addition to being used as a medicine, piperine toxicity to mammals, low residue and extensive biologi- is also an important organic synthetic building blocks cal activity [13–15]. At present, there are many varieties of plant essential oils, and their applications are limited to the contact, fumigation and repellent of pests in con- *Correspondence: caoxiufang@mail.hzau.edu.cn College of Science, Huazhong Agricultural University, Wuhan 430070, fined environments such as greenhouses and warehouses China [16–18]. In addition, essential oils can also be used as © The Author(s) 2020. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creat iveco mmons .org/licen ses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creat iveco mmons .org/publi cdoma in/ zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data. Wang et al. BMC Chemistry (2020) 14:24 Page 2 of 12 synergists, solubilizers, flavoring agents and chemi - General synthesis of precursors cal pesticides. However, most of essential oils are vola- The key precursors including (E)-3-(benzo[d][1,3]dioxol- tile, unstable to light and heat, easy to decompose, etc. 5-yl)acrylic acid (n = 1) and piperic acid (n = 2) were pre- Therefore, if the rational derivatization of essential oil pared using a similar methods reported in the references molecules can be based on retaining their activity, the [21, 22]. application of plant essential oils will undoubtedly be a significant development. Recently, during the course of our research for functional molecules based on natural General synthetic procedures for target compounds essential oils [19, 20], a series of essential oil-oriented The corresponding acid bearing 1,3-benzodioxole derivatives have been synthesized and approved to unit (0.005  mol), phenolic compound (0.005  mol) and exhibit insecticidal or fungicidal activities, which suggest acetonitrile (30–60  mL) were added to a 150  mL dry that these natural essential oils might contribute to the round bottom flask, and 0.3  g of 4-dimethylamino - biological functions. pyridine was added as a catalyst, and 1.5  g of N,N′- Based on this investigation, a series of piperine-ori- dicyclohexylcarbodiimide was further added as a ented derivatives derived from natural phenolic com- condensing agent. The reaction was stirred at room tem - pounds existed in essential oils were designed and perature to 40  °C for additional hours, and TLC traced synthesized as following strategy in Fig. 1. So, in order to the reaction to completion. After the completion of the explore the potential applications for these novel essential reaction, the solution was dissolved in water (20  mL), oil derivatives, we report herein the synthesis and charac- and the aqueous solution was extracted with ethyl acetate terization of twenty-one essential oil derivatives via sim- (30  mL × 2) twice. The combined organic phases were ple reaction, and their antifungal activities against several washed with 5% N a CO solution (30 mL × 2) and water 2 3 phytopathogenic fungi have also been fully investigated. to neutrality and dried over anhydrous Na SO . After fil - 2 4 tration and concentration, the corresponding crude com- Materials and methods pound were obtained, which were purified by silica gel Instrumentation and chemicals column-chromatography (ethyl acetate/petroleum ether) All chemicals or reagents used for syntheses were of or recrystallization to give pure compounds. analytical reagent, and used directly without purifica - tion. Melting points (m.p.) were determined on a RY-2 apparatus and are uncorrected. H NMR spectra were 5‑Isopropyl‑2‑methylphenyl benzo[d][1,3] recorded on a Brucker spectrometer at 600  MHz with dioxole‑5‑carboxylate (1a) the CDCl as the solvent and TMS as the internal stand- H NMR (600 MHz, C DCl ): δ = 7.85 (dd, J = 8.2, 1.8  Hz, 3 3 ard. C NMR spectra were recorded on a Brucker spec- 1H), 7.64 (d, J = 1.8 Hz, 1H), 7.19 (d, J = 7.8 Hz, 1H), 7.05 trometer at 150  MHz with CDCl as the solvent. Mass (dd, J = 7.8, 1.8 Hz, 1H), 6.98 (d, J = 1.8 Hz, 1H), 6.92 (d, spectra were performed on a Waters ACQUITY U PLC J = 8.2  Hz, 1H), 6.08 (s, 2H), 2.93–2.88 (m, 1H), 2.18 (s, ® 13 H-CLASS PDA (Waters ) instrument. Column chroma- 3H), 1.25 (d, J = 6.6 Hz, 6H); C NMR (150 MHz, CDCl ): tography was carried out using silica gel 100–200  mesh. δ = 164.39, 152.25, 149.59, 148.23, 148.04, 131.03, 127.51, Analytical thin-layer chromatography (TLC) was carried 126.26, 124.26, 123.63, 120.04, 110.08, 108.31, 102.08, out on precoated plates, and spots were visualized with 33.74, 24.07, 15.98; MS (ESI) m/z 299.6 (M+H) , calcd. ultraviolet light.for C H O m/z = 299.1. 18 19 4 Fig. 1 Design strategy of piperine-based essential oils derivatives W ang et al. BMC Chemistry (2020) 14:24 Page 3 of 12 2‑Isopropyl‑5‑methylphenyl benzo[d][1,3] 152.39, 151.72, 147.98, 132.37, 126.49, 111.97, 110.07, dioxole‑5‑carboxylate (1b) 109.25, 108.30, 102.01, 55.75, 29.52; MS (ESI) m/z 337.4 1 + H NMR (600 MHz, C DCl ): δ = 7.84–7.82 (m, 1H), 7.62 (M+Na) , calcd. for C H NaO m/z = 337.1. 3 17 14 6 (s, 1H), 7.26–7.20 (m, 1H), 7.05 (d, J = 7.4 Hz, 1H), 6.94– 6.88 (m, 3H), 6.06 (s, 2H), 3.06–3.01 (m, 1H), 2.33 (s, 3H), 2‑(Methoxycarbonyl)phenyl benzo[d][1,3] 1.20 (d, J = 7.2  Hz, 6H); C NMR (150  MHz, C DCl ): dioxole‑5‑carboxylate (1g) δ = 164.72, 152.15, 148.15, 147.93, 137.17, 136.60, 127.10, H NMR (600 MHz, C DCl ): δ = 8.06 (dd, J = 7.8, 1.8  Hz, 126.43, 126.12, 123.51, 122.90, 109.91, 108.20, 101.96, 1H), 7.85 (dd, J = 8.2, 1.8 Hz, 1H), 7.64 (d, J = 1.6 Hz, 1H), 27.29, 22.67, 20.85; MS (ESI) m/z 299.5 (M+H) , calcd. 7.61–7.59 (m, 1H), 7.36–7.34 (m, 1H), 7.22 (dd, J = 8.1, for C H O m/z = 299.1. 18 19 4 0.8 Hz, 1H), 6.92 (d, J = 8.2 Hz, 1H), 6.08 (s, 2H), 3.76 (s, 3H); C NMR (150  MHz, CDCl ): δ = 165.04, 164.68, Benzo[d][1,3]dioxol‑5‑yl benzo[d][1,3]dioxole‑5‑carboxylate 152.19, 150.83, 147.89, 133.80, 131.87, 126.36, 126.00, (1c) 124.00, 123.48, 123.40, 110.07, 108.22, 101.94, 52.21; H NMR (600 MHz, CDCl ): δ = 7.80 (dd, J = 8.2, 1.8  Hz, MS (ESI) m/z 323.4 (M+Na) , calcd. for C H NaO 16 12 6 1H), 7.59 (d, J = 1.8  Hz, 1H), 6.90 (d, J = 8.2  Hz, 1H), m/z = 323.1. 6.81 (d, J = 8.4 Hz, 1H), 6.71 (d, J = 2.4 Hz, 1H), 6.63 (dd, J = 8.4, 2.4  Hz, 1H), 6.08 (s, 2H), 6.00 (s, 2H); C NMR 5‑Isopropyl‑2‑methylphenyl 3‑(benzo[d][1,3]dioxol‑5‑yl) (150 MHz, CDCl ): δ = 164.82, 152.20, 147.90, 145.36, acrylate (2a) 126.19, 123.30, 114.06, 109.92, 108.15, 108.01, 103.92, + H NMR (600  MHz, C DCl ): δ = 7.79 (d, J = 16.2  Hz, 101.97, 101.71; MS (ESI) m/z 287.5 (M+H) , calcd. for 3 1H), 7.17 (d, J = 7.8  Hz, 1H), 7.11–7.02 (m, 3H), 6.93 C H O m/z = 287.0. 15 11 6 (s, 1H), 6.03 (s, 2H), 6.84 (d, J = 8.0  Hz, 1H), 6.48 (d, J = 15.6 Hz, 2H), 6.03 (s, 2H), 2.91–2.87 (m, 1H), 1.24 (d, 4‑Allyl‑2‑methoxyphenyl benzo[d][1,3]dioxole‑5‑carboxylate J = 7.2  Hz, 6H); C NMR (150 MHz, C DCl ): δ = 165.41, (1d) 149.94, 149.33, 148.03, 146.11, 128.66, 127.37, 124.85, H NMR (600  MHz, CDCl ): δ = 7.83 (dd, J = 8.2, 124.08, 119.84, 115.08, 106.60, 101.65, 33.58, 23.92, 1.8 Hz, 1H), 7.62 (d, J = 1.8 Hz, 1H), 7.26 (s, 1H), 7.04 (d, 15.86; MS (ESI) m/z 325.6 (M+H) , calcd. for C H O 20 21 4 J = 8.0 Hz, 1H), 6.89 (d, J = 8.2 Hz, 1H), 6.82 (d, J = 1.8 Hz, m/z = 325.1. 1H), 6.06 (s, 2H), 6.00–5.95 (m, 1H), 5.16–5.06 (m, 2H), 3.80 (s, 3H), 3.40 (d, J = 7.2 Hz, 2H); C NMR (150 MHz, 2‑Isopropyl‑5‑methylphenyl 3‑(benzo[d][1,3]dioxol‑5‑yl) CDCl ): δ = 164.24, 152.02, 151.10, 147.80, 138.96, acrylate (2b) 138.21, 137.11, 126.27, 123.40, 122.66, 120.71, 116.12, H NMR (600  MHz, CDCl ): δ = 7.78 (d, J = 16.2  Hz, 112.83, 110.12, 108.09, 101.88, 55.89, 40.12; MS (ESI) m/z 1H), 7.22 (d, J = 7.8  Hz, 1H), 7.13–7.01 (m, 4H), 6.87 (d, 335.6 (M+Na) , calcd. for C H NaO m/z = 335.1. 18 16 5 d, J = 7.8  Hz, 1H), 6.48 (d, J = 15.6  Hz, 1H), 6.03 (s, 2H), 3.05–3.01 (m, 1H), 2.33 (s, 3H) 1.21 (d, J = 7.2  Hz, 6H); 2,6‑Dimethoxyphenyl benzo[d][1,3]dioxole‑5‑carboxylate C NMR (150 MHz, C DCl ): δ = 165.88, 149.95, 148.45, (1e) 147.99, 146.12, 137.21, 136.55, 128.65, 127.07, 124.87, H NMR (600 MHz, C DCl ): δ = 7.86 (dd, J = 8.2, 1.8  Hz, 122.81, 115.16, 108.63, 106.63, 101.65, 27.16, 23.08, 1H), 7.66 (d, J = 1.8  Hz, 1H), 7.17–7.16 (m, 1H), 6.89 20.86; MS (ESI) m/z 325.5 (M+H) , calcd. for C H O 20 21 4 (d, J = 8.2  Hz, 1H), 6.64 (d, J = 8.4  Hz, 1H), 6.06 (s, 2H), m/z = 325.1. 13 1 3.80 (s, 6H); C NMR H NMR (150  MHz, CDCl ): δ = 163.88, 152.57, 151.98, 147.76, 128.95, 126.41, 126.23, 123.32, 110.29, 108.07, 104.95, 101.85, 56.19; MS (ESI) Benzo[d][1,3]dioxol‑5‑yl 3‑(benzo[d][1,3]dioxol‑5‑yl)acrylate m/z 325.5 (M+Na) , calcd. for C H NaO m/z = 325.1. (2c) 16 14 6 H NMR (600  MHz, C DCl ): δ = 7.68 (d, J = 15.6  Hz, 1H), 7.04–6.97 (m, 2H), 6.77 (d, J = 8.0  Hz, 1H), 6.73 (d, 2‑Acetyl‑5‑methoxyphenyl benzo[d][1,3] J = 8.4  Hz, 1H), 6.61 (d, J = 2.4  Hz, 1H), 6.53 (dd, J = 8.4, dioxole‑5‑carboxylate (1f ) 2.4  Hz, 1H), 5.96 (s, 2H), 5.92 (s, 2H). 5.84 (s, 1H); C H NMR (600 MHz, CDCl ): δ = 7.89 (d, J = 8.8  Hz, 1H), NMR (150  MHz, C DCl ): δ = 165.90, 150.02, 148.46, 7.84 (dd, J = 8.2, 1.8 Hz, 1H), 7.62 (d, J = 1.8 Hz, 1H), 6.92 148.00, 146.33, 145.29, 145.15, 128.60, 124.93, 114.97, (d, J = 8.2 Hz, 1H), 6.87 (dd, J = 8.8, 2.4 Hz, 1H), 6.70 (d, 114.01, 108.65, 108.00, 106.60, 103.86, 101.69, 101.18; J = 2.4  Hz, 1H), 6.08 (s, 3H), 3.87 (s, 3H), 2.49 (s, 3H); MS (ESI) m/z 313.5 (M+H) , calcd. for C H O 17 13 6 C NMR (150 MHz, CDCl ): δ = 195.68, 164.42, 163.73, m/z = 313.1. Wang et al. BMC Chemistry (2020) 14:24 Page 4 of 12 4‑Allyl‑2‑methoxyphenyl 3‑(benzo[d][1,3]dioxol‑5‑yl)acrylate 1H), 5.93 (s, 2H), 2.83–2.79 (m, 1H), 2.08 (s, 3H), 1.16 (d, (2d) J = 14.6 Hz, 6H); C NMR (150 MHz, CDCl ): δ = 165.51, H NMR (600 MHz, CDCl ): δ = 7.70 (d, J = 15.6 Hz, 1H), 149.31, 148.79, 148.35, 148.04, 146.69, 141.25, 130.88, 7.05–6.92 (m, 3H), 6.79–6.69 (m, 3H), 6.42 (d, J = 15.9 Hz, 130.40, 127.42, 124.33, 124.11, 123.34, 119.88, 119.20, 1H), 5.98–5.85 (m, 3H), 5.09–5.00 (m, 2H), 3.76 (s, 3H), 108.63, 105.93, 101.50, 33.61, 24.08, 15.92; MS (ESI) m/z 3.33 (d, J = 6.7  Hz, 2H); C NMR (150  MHz, C DCl ): 373.5 (M+Na) , calcd. for C H NaO m/z = 373.2. 3 22 22 4 δ = 165.32, 151.04, 149.87, 148.41, 146.15, 138.92, 138.03, 137.10, 128.76, 124.83, 122.67, 120.71, 116.15, 114.97, 2‑Isopropyl‑5‑methylphenyl 5‑(benzo[d][1,3]dioxol‑5‑yl) 112.76, 108.61, 106.65, 101.62, 55.90, 40.14; MS (ESI) m/z penta‑2,4‑dienoate (3b) 361.6 (M+Na) , calcd. for C H NaO m/z = 361.1. H NMR (600 MHz, C DCl ): δ = 7.55–7.51 (m, 1H), 7.15 20 18 5 3 (d, J = 7.8  Hz, 1H), 6.96–6.95 (m, 2H), 6.87–6.86 (m, 2,6‑Dimethoxyphenyl 3‑(benzo[d][1,3]dioxol‑5‑yl)acrylate 2H), 6.79 (s, 1H), 6.74–6.71 (m, 2H), 6.09 (d, J = 15.0  Hz, (2e) 1H), 5.92 (s, 2H), 2.96–2.91 (m, 1H), 2.24 (s, 3H), 1.12 (d, H NMR (600  MHz, C DCl ): δ = 7.72 (d, J = 15.6  Hz, J = 6.6  Hz, 6H); C NMR (150 MHz, C DCl ): δ = 166.02, 3 3 1H), 7.10–7.07 (m, 1H), 7.03 (d, J = 1.8  Hz, 1H), 7.00 148.81, 148.36, 147.97, 146.71, 141.32, 137.22, 136.60, (d, J = 7.5  Hz, 1H), 6.76 (d, J = 7.8  Hz, 1H), 6.57 (d, 130.40, 127.11, 126.46, 124.33, 123.36, 122.87, 119.27, J = 9.0 Hz, 2H), 6.48 (d, J = 16.2 Hz, 1H), 5.96 (s, 2H), 3.76 108.64, 105.93, 101.52, 27.17, 22.75, 20.94; MS (ESI) m/z (s, 6H); C NMR (150 MHz, CDCl ): δ = 164.89, 152.51, 373.5 (M+Na) , calcd. for C H NaO m/z = 373.2. 3 22 22 4 149.82, 148.37, 146.23, 128.85, 126.22, 124.83, 114.83, 108.59, 106.69, 104.92, 101.60, 56.21; MS (ESI) m/z 351.5 Benzo[d][1,3]dioxol‑5‑yl 5‑(benzo[d][1,3]dioxol‑5‑yl) (M+Na) , calcd. for C H NaO m/z = 351.1. penta‑2,4‑dienoate (3c) 18 16 6 H NMR (600  MHz, C DCl ): δ = 7.57 (dd, J = 15.2, 2‑Acetyl‑5‑methoxyphenyl 3‑(benzo[d][1,3]dioxol‑5‑yl) 11.0  Hz, 1H), 7.02 (d, J = 1.6  Hz, 1H), 6.94 (dd, J = 8.0, acrylate (2f ) 1.6 Hz, 1H), 6.88 (d, J = 15.0 Hz, 1H), 6.81–6.77 (m, 3H), H NMR (600 MHz, CDCl ): δ = 7.89 (d, J = 9.0  Hz, 1H), 6.66 (d, J = 2.4 Hz, 1H), 6.58 (dd, J = 8.4, 2.4 Hz, 1H), 6.09 7.82 (d, J = 15.6  Hz, 1H), 7.13 (d, J = 1.6  Hz, 1H), 7.11– (d, J = 15.2  Hz, 1H), 5.99 (d, J = 9.6  Hz, 4H); C NMR 7.09 (m, 1H), 6.87 (dd, J = 8.6, 2.4  Hz, 2H), 6.70 (s, 1H), (150 MHz, CDCl ): δ = 165.84, 148.81, 148.34, 147.95, 6.52 (d, J = 15.6  Hz, 1H), 6.06 (s, 2H), 3.88 (s, 3H), 2.54 146.76, 145.23, 145.15, 141.34, 130.37, 124.27, 123.27, (s, 3H); C NMR (150 MHz, CDCl ): δ = 195.96, 165.36, 119.07, 113.99, 108.59, 107.96, 105.95, 103.86, 101.65, 163.69, 151.51, 150.14, 148.45, 147.07, 132.26, 128.51, 101.45; MS (ESI) m/z 339.2 (M+H) , calcd. for C H O 19 15 6 125.18, 123.68, 114.68, 111.89, 109.12, 108.64, 106.71, m/z = 339.1. 101.69, 55.74, 29.61; MS (ESI) m/z 363.5 (M+Na) , calcd. for C H NaO m/z = 363.1. 4‑Allyl‑2‑methoxyphenyl 5‑(benzo[d][1,3]dioxol‑5‑yl) 19 16 6 penta‑2,4‑dienoate (3d) Methyl 2‑((3‑(benzo[d][1,3]dioxol‑5‑yl)acryloyl)oxy)benzoate H NMR (600  MHz, C DCl ): δ = 7.64–7.60 (m, 1H), (2g) 7.16–7.13 (m, 1H), 7.03 (d, J = 1.8  Hz, 1H), 6.94 (dd, H NMR (600 MHz, CDCl ): δ = 7.97 (d, J = 9.0  Hz, 1H), J = 8.0, 1.8  Hz, 1H), 6.87 (d, J = 15.6  Hz, 1H), 6.81–6.78 7.73 (d, J = 15.6  Hz, 1H), 7.53–7.50 (m, 1H), 7.27 (d, (m, 2H), 6.63 (d, J = 8.4 Hz, 2H), 6.22 (d, J = 15.2 Hz, 1H), J = 8.0 Hz, 1H), 7.19 (s, 2H), 7.11 (d, J = 7.8 Hz, 1H), 7.04– 6.00 (s, 2H), 3.82 (s, 6H); C NMR (150  MHz, C DCl ): 7.00 (m, 2H), 6.77 (d, J = 8.0 Hz, 1H), 6.45 (d, J = 15.6 Hz, δ =164.83, 152.51, 148.68, 148.31, 146.65, 140.92, 130.53, 1H), 5.96 (s, 2H), 3.77 (s, 3H); C NMR (150  MHz, 128.80, 126.14, 124.54, 123.14, 119.03, 108.55, 105.96, CDCl ): δ = 165.61, 165.14, 150.65, 149.99, 148.43, 104.92, 101.42, 56.19; MS (ESI) m/z 365.4 (M+H) , calcd. 146.55, 133.79, 131.77, 128.67, 125.94, 125.01, 123.91, for C H O m/z = 365.1. 22 21 5 123.56, 114.87, 108.61, 106.70, 101.66, 52.25; MS (ESI) m/z 349.4 (M+Na) , calcd. for C H NaO m/z = 349.1. 2,6‑Dimethoxyphenyl 5‑(benzo[d][1,3]dioxol‑5‑yl) 18 14 6 penta‑2,4‑dienoate (3e) 5‑Isopropyl‑2‑methylphenyl 5‑(benzo[d][1,3]dioxol‑5‑yl) H NMR (600  MHz, C DCl ): δ = 7.64–7.60 (m, 1H), penta‑2,4‑dienoate (3a) 7.16–7.13 (m, 1H), 7.03 (d, J = 1.8  Hz, 1H), 6.94 (dd, H NMR (600  MHz, C DCl ): δ = 7.83–7.79 (m, J = 15.2, J = 8.0, 1.8  Hz, 1H), 6.87 (d, J = 15.6  Hz, 1H), 6.81–6.78 10.9 Hz, 1H), 7.09 (d, J = 7.8 Hz, 1H), 6.96–6.95 (m, 3H), (m, 2H), 6.63 (d, J = 8.4 Hz, 2H), 6.22 (d, J = 15.2 Hz, 1H), 6.88–6.80 (m, 3H), 6.75–6.70 (m, 2H), 6.09 (d, J = 15.2 Hz, 6.00 (s, 2H), 3.82 (s, 6H); C NMR (150  MHz, C DCl ): 3 W ang et al. BMC Chemistry (2020) 14:24 Page 5 of 12 107.55, 104.93, 100.43, 51.20; MS (ESI) m/z 375.5 δ = 164.83, 152.51, 148.68, 148.31, 146.65, 140.92, 130.53, (M+Na) , calcd. for C H NaO m/z = 375.1. 128.80, 126.14, 124.54, 123.14, 119.03, 108.55, 105.96, 20 16 6 104.92, 101.42, 56.19; MS (ESI) m/z 377.4 (M+Na) , Biological assay calcd. for C H NaO m/z = 377.1. 20 18 6 The in vitro fungicidal activities of the target compounds 1a–3g against Rhizoctonia solani, Fusarium gramine- 2‑Acetyl‑5‑methoxyphenyl 5‑(benzo[d][1,3]dioxol‑5‑yl) arum, Phomopsis adianticola, Alternaria tenuis Nees, penta‑2,4‑dienoate (3f ) Phytophthora capsici and Gloeosporium theae-sinensis H NMR (600 MHz, CDCl ): δ = 7.86 (d, J = 8.8  Hz, 1H), were evaluated using mycelium growth rate test, and all 7.63 (dd, J = 15.2, 11.0  Hz, 1H), 7.03 (d, J = 1.6  Hz, 1H), the procedure for bioassay were according to the meth- 6.98–6.87 (m, 3H), 6.86–6.78 (m, 4H), 6.66 (d, J = 2.5  Hz, ods reported in literature [23]. 1H), 6.18 (d, J = 15.2  Hz, 1H), 6.00 (s, 2H), 3.85 (s, 3H), 2.51 (s, 3H); C NMR (150  MHz, CDCl ): δ = 192.87, Results and discussion 165.23, 163.65, 151.54, 148.89, 148.36, 147.49, 141.78, Synthesis 132.19, 130.34, 124.26, 123.71, 117.79, 111.86, 109.06, A series of novel compounds 1a–g, 2a–g and 3a–g 108.60, 105.98, 101.47, 55.71, 29.69; MS (ESI) m/z 389.4 derived from natural phenolic compounds existed in (M+Na) , calcd. for C H NaO m/z = 389.1. 21 18 6 essential oils based on piperine scaffold can be syn - thesized by a mild and simple method as described in Methyl 2‑((5‑(benzo[d][1,3]dioxol‑5‑yl)penta‑2,4‑dienoyl) Scheme 1. In brief, the intermediate (E)-3-(benzo[d][1,3] oxy)benzoate (3g) dioxol-5-yl)acrylic acid (n = 1) can be prepared using H NMR (600 MHz, C DCl ): δ = 7.95 (dd, J = 7.8, 1.8  Hz, piperonal as starting materials [21], and the other inter- 1H), 7.59–7.46 (m, 2H), 7.27–7.21 (m, 1H), 7.08 (dd, mediate piperic acid (n = 2) was synthesized via basic J = 8.2, 0.8  Hz, 1H), 6.95 (d, J = 1.6  Hz, 1H), 6.87 (dd, hydrolysis reaction of piperine [22]. Then, all three acids J = 8.0, 1.6  Hz, 1H), 6.81 (d, J = 15.6  Hz, 1H), 6.76–6.68 were coupling with various essential oils molecules to (m, 2H), 6.12 (d, J = 15.2  Hz, 1H), 5.92 (s, 4H), 3.76 (s, obtain the corresponding esters using an optimization 2H); C NMR (150  MHz, CDCl ): δ = 164.51, 164.12, method. 149.61, 147.76, 147.31, 145.94, 140.29, 132.71, 130.70, 129.39, 124.85, 123.40, 122.89, 122.53, 122.22, 118.00, Scheme 1 Synthetic route for intermediates and target molecules Wang et al. BMC Chemistry (2020) 14:24 Page 6 of 12 Table 1 The optimal reaction conditions of  piperic acid Table 2, and their chemical structures and basic physico- and carvacrol chemical properties were summarized in “Materials and methods”. Entry Catalytic Solvent Temperature Time (h) Yield (%) system (°C) Spectrum analyses 1 DCC/DMAP THF 40 6 47.47 The structures of all target compounds 1a– 3g were con- 2 DCC/DMAP DCM 40 6 78.42 1 13 firmed by H NMR, C NMR (Additional file  1) and 3 DCC/DMAP MeCN 40 6 83.40 mass spectrometry, and their structures were well con- 4 DCC/DMAP MeCN 60 6 68.55 sistent with all the spectral data. A representative H 5 DCC/DMAP MeCN 90 6 65.46 NMR spectrum of 1c is shown in Fig. 2, and each hydro- 6 EDCI/HOBT MeCN 40 6 NR gen shows a characteristic absorption peak. The methyl - 7 CDI/DIPEA MeCN 40 6 NR ene group on the piperine skeleton was not affected by other H in the ortho position, and a single peak appeared at 6.06  ppm, and the H of the benzene ring showed between 7.81 and 6.62 ppm. To achieve the above goal for these essential oil deriva- tives, the initial experiment was optimized, and the dif- Biological activity ferent reaction conditions have been explored (Table  1). Primary screening test As can be seen from Table  1 (Entry 6 and 7), when the In this study, all essential oil derivatives 1a–g, 2a–g, and condensation system is EDCI/HOBT or CDI/DIPEA, 3a–g were screened for their antifungal activities in vitro TLC analysis showed that no obvious product was pro- against six common plant pathogenic fungi (Rhizocto- duced, however, the yields are improved when the con- nia solani, Fusarium graminearum, Alternaria tenuis densation reactions are performed under the DCC/ Nees, Gloeosporium theae-sinensis, Phytophthora capsici, DMAP system. With this condition (DCC/DMAP) Phomopsis adianticola), and the preliminary screening in hand, the solvent is further screened, and an equal results were outlined in Table 3. volume of acetonitrile, tetrahydrofuran and dichlo- Generally, as shown in Table  3, the preliminary assay romethane are used as solvents. The reaction time and illustrated that some compounds of the essential oil temperature are the same. The relationship between sol - derivatives based on piperine displayed good inhibi- vent and yield was obtained, as shown in Table  1, when tory activities against some tested fungal strains, and acetonitrile was the solvent, the yield was the highest. In we also can find that some of the target compounds order to investigate the effect of the target compound have better inhibitory activities than piperine and car- yield on the reaction temperature, the experiment was bendazim at the concentration of 100  µg/mL. Nota- carried out at a reaction temperature of 40  °C, 60  °C, bly, six compounds displayed fungicidal activity more and 90  °C, respectively. The results show that the yield than 40% against Rhizoctonia solani, especially com- gradually decreases with increasing temperature, and pound 1f displayed an 65.00% inhibition rate, better the yield is highest at 40  °C. Finally, we determined the than that of piperine (63.13%). Three compounds dis - optimal synthetic conditions for the synthesis of pepper played fungicidal activity more than 40% against Fusar- acid-directed essential oil derivatives: DCC/DMAP is a ium graminearum, except compound 2b displayed catalytic condensation system, the solvent is acetonitrile, an 62.61% inhibition rate, better than that of piperine the reaction temperature is 40  °C, and the yield of the (53.04%). Four compounds displayed fungicidal activity target compound is 83.40%. more than 40% against Alternaria tenuis Nees, except All of the new natural phenolic derivatives were syn- compound 1d displayed 71.07% inhibition rate, better thesized according to the optimal conditions described than that of the piperine (66.12%) and carbendazim above, and the structures of all the obtained compounds (13.22%). Five compounds displayed fungicidal activ- in this study were confirmed by satisfactory spectral ity more than 40% against Gloeosporium theae-sinensis, 1 13 analysis, including H NMR, C NMR, ESI–MS. The 2b displayed an 66.92% inhibition rate, which is less chemical formulas of all compounds were described in than the activity of piperine (76.92%). Four compounds W ang et al. BMC Chemistry (2020) 14:24 Page 7 of 12 Table 2 The chemical structure of target compounds 1a–3g Compd. no.Structure Appearance MP (°C) Yield (%) Yellowish 1a –83.4 liquid 1b White solid 61–6366.0 1c White solid 117–120 42.3 1d Yellowishsolid 68–7278.85 1e White solid 158–160 57.7 1f White solid 116–120 88.46 1g White solid 93–9683.90 Brownish 2a yellow 45–4981.20 semisolid 2b White solid 70–7375.6 2c White solid 134–137 80.3 2d White solid 121–125 77.8 2e White solid 174–178 85.6 2f White solid 137–141 77.8 Wang et al. BMC Chemistry (2020) 14:24 Page 8 of 12 Table 2 (continued) Compd. no.Structure Appearance MP (°C) Yield (%) 2g White solid 122–12584.6 Yellow 3a 68–7255.8 semisolid 3b Yellowish solid 89–9173.5 3c Yellowish solid 136–138 59.3 3d Yellowish solid 109–113 62.13 Orange-yellow 3e 155–158 53.8 solid Orange-yellow 3f 127–130 53.0 solid 3g Yellow solid 115–118 40.06 displayed fungicidal activity more than 40% against activities, we thus selected some compounds like 1a, Phytophthora capsici, except compound 2b displayed 1b, 1c, 1d, 1g, 2a, 2b, 2g to have further exploration an 100% inhibition rate, which is much greater than in such a situation, and compared the values of IC the piperine (41.88%) and carbendazim (34.27%). Four with piperine and carbendazim at different concentra - compounds displayed fungicidal activity more than tions. The fungicidal activities expressed as IC values 40% against Phomopsis adianticola, except compound for highly potential compounds are listed in Table  4, 2b displayed an 100% inhibition rate, far superior to the which indicated some compounds had good inhibi- piperine (29.63%). tory effects. As shown in Table  4, compounds 1a, 1g, 2b, 2g (IC = 11.21, 87.66, 7.79, 97.84  μg/mL) all dis- played good inhibitory effects on Phytophthora cap - Secondary screening test sici compared with the positive control carbendazim The preliminary assay indicated many of the target (IC > 100  μg/mL). Compounds 1a and 2b displayed compounds exhibited good fungicidal activities com- good inhibitory effects compared with the piperine pared to the commercial fungicide carbendazim, in (IC = 34.87 μg/mL). In particular, 2b exhibits a broad order to further investigate the potential fungicidal spectrum of bacteriostatic activity. W ang et al. BMC Chemistry (2020) 14:24 Page 9 of 12 Fig. 2 Representative H NMR spectra for compound 1c 1 13 In addition, the Fig.  3 indicated the inhibition effects were characterized by H-NMR, C-NMR and ESI– of target compounds 1a, 2b on Phomopsis adianticola MS spectra analyses, and potential bioactivity was also compared with that of piperine and carbendazim, which assessed. Preliminary bioassay results indicate that some confirmed that the compounds 1a and 2b displayed new compounds show better fungistatic activity than pip- the superior fungicidal activities on the Phomopsis adi- erine. Among them, compound 2b exhibits a broad spec- anticola at different concentrations of 12.5, 25, 50, 100, trum of fungicidal activity, and it is hoped that further 200 µg/mL. development of a new piperine-oriented agrochemicals. Conclusions In summary, 21 piperine-directed essential oil derivatives have been designed, synthesized and evaluated as poten- tial fungicides. The structures of all obtained molecules Wang et al. BMC Chemistry (2020) 14:24 Page 10 of 12 Table 3 In vitro fungicidal activity of target compounds 1a–3g Entry Compd. no. In vitro fungicidal activity (%)/100 µg/mL a a a a a a R.S F.G A.T G.T P.C P.A 1 1a 21.88 18.26 47.11 51.54 68.38 68.89 2 1b 29.69 36.52 52.89 35.77 31.62 61.85 3 1c 57.50 0.00 −1.65 4.62 14.53 3.70 4 1d 30.63 17.39 71.07 52.31 24.79 40.00 5 1e 17.50 15.65 25.62 27.69 29.06 3.70 6 1f 65.00 31.74 33.06 26.92 30.77 47.41 7 1g 20.94 22.61 7.44 0.00 47.86 23.70 8 2a 18.13 34.78 34.71 43.08 35.90 45.19 9 2b 57.50 62.61 52.07 66.92 100 100.00 10 2c 35.94 18.26 7.44 15.38 35.90 −3.70 11 2d 37.19 19.13 7.44 18.08 38.46 0.00 12 2e 63.75 21.74 −3.31 3.08 27.35 3.70 13 2f 40.94 20.87 2.48 13.85 33.33 −2.22 14 2g 46.56 11.30 9.92 60.77 47.01 29.63 15 3a 30.94 46.09 23.97 30.77 33.33 18.52 16 3b 25.00 35.65 25.62 15.38 23.08 16.30 17 3c 20.94 35.65 13.22 15.00 5.98 3.70 18 3d 21.25 45.22 24.79 38.46 19.66 17.04 19 3e 15.63 33.04 16.53 24.62 24.79 18.52 20 3f 7.81 37.09 16.53 23.08 0.85 29.63 21 3g 18.13 24.35 17.36 30.77 15.38 29.63 22 Piperine 63.13 53.04 66.12 76.92 41.88 29.63 23 Carbendazim 100.00 100.00 13.22 100.00 34.27 100.00 R.S, Rhizoctonia solani; F.G - Fusarium graminearum, A.T, Alternaria tenuis Nees; G.T, Gloeosporium theae-sinensis; P.C, Phytophthora capsici; P.A, Phomopsis adianticola Table 4 The IC of some compounds against the plant pathogen fungi Entry Compd. no. IC (µg/mL) R.S F.G A.T G.T P.C P.A 1 1a 39.92 156.99 43.06 64.65 11.21 35.67 2 1b 29.29 > 200 121.77 >200 – 45.75 3 1c 69.06 – – – – – 4 1d – – – 142.36 – – 5 1g – – – – 87.66 – 6 2a 89.50 – – – – 72.66 7 2b 39.46 38.83 12.02 22.55 7.79 8.84 8 2g – – >200 81.95 97.54 – 9 Piperine 89.50 >200 116.77 42.84 34.87 84.88 10 Carbendazim 2.94 3.30 173.18 2.86 114.42 3.73 IC —compound concentration required to inhibit colony growth by 50% R.S, Rhizoctonia solani; F.G, Fusarium graminearum; A.T, Alternaria tenuis Nees; G.T, Gloeosporium theae-sinensis; P.C, Phytophthora capsici; P.A, Phomopsis adianticola Carbendazim, used as positive control W ang et al. BMC Chemistry (2020) 14:24 Page 11 of 12 Fig. 3 Inhibition activity of compounds 1a, 2b, piperine and carbendazim on Phomopsis adianticola. a–e The concentration of compounds 1a, 2b, piperine and carbendazim are 12.5, 25, 50, 100, and 200 µg/mL; CK blank control Competing interests Supplementary information The authors declare no conflicts of interest. Supplementary information accompanies this paper at https ://doi. org/10.1186/s1306 5-020-00676 -4. Received: 15 November 2019 Accepted: 16 March 2020 1 13 Additional file 1. H NMR, and C NMR spectra for the target compounds. References 1. Mujumdar AM, Dhuley JN, Deshmukh VK, Raman PH, Thorat SL, Naik SR Abbreviations (1990) Eec ff t of piperine on pentobarbitone induced hypnosis in rats. EOs: Essential oils; m.p.: Melting points; TLC: Analytical thin-layer chromatog- Indian J Exp Biol 28:486–487 raphy; R.S: Rhizoctonia solani; F.G: Fusarium graminearum; A.T: Alternaria tenuis 2. 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Fitoterapia (synthesized the selected derivatives), HX (synthesized the selected deriva- 76:296–300 tives), DS (bioactivity evaluation), XC (proposed the project and explained the 6. Yasir A, Ishtiaq S, Jahangir M, Ajaib M, Salar U, Khan KM (2018) Biology- analyses, and revised the manuscript). All authors read and approved the final oriented synthesis (BIOS) of piperine derivatives and their comparative manuscript. analgesic and antiinflammatory activities. Med Chem 14:269–280 7. Lee SA, Hong SS, Han XH, Hwang JS, Oh GJ, Lee KS, Lee MK, Hwang BY, Ro Funding JS (2005) Piperine from the fruits of Piper longum with inhibitory effect on Financial support from the National Innovation and Entrepreneurship Training monoamine oxidase and antidepressant-like activity. Chem Pharm Bull Program for College Students (201910504109) is gratefully acknowledged, 53:832–835 and the authors also appreciated for Huazhong Agricultural University for 8. 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Mann RS, Tiwari S, Smoot JM, Rouseff RL, Stelinski LL (2012) Repellency Springer Nature remains neutral with regard to jurisdictional claims in pub- and toxicity of plant-based essential oils and their constituents against lished maps and institutional affiliations. Diaphorina citri Kuwayama (Hemiptera: Psyllidae). J Appl Entomol 136:87–96 Ready to submit your research ? Choose BMC and benefit from: fast, convenient online submission thorough peer review by experienced researchers in your field rapid publication on acceptance support for research data, including large and complex data types • gold Open Access which fosters wider collaboration and increased citations maximum visibility for your research: over 100M website views per year At BMC, research is always in progress. Learn more biomedcentral.com/submissions

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