molecules Molecules Molecules Molecules 1420-3049 MDPI 10.3390/molecules17043969 molecules-17-03969 Article Synthesis and Herbicidal Activity Evaluation of Novel β-Carboline Derivatives Weng Qunfang 1 2 Huang Jingfei 1 2 Zeng Yong 1 2 Deng Yueye 1 2 Hu Meiying 1 2 * Key Laboratory of Pesticide and Chemical Biology, Ministry of Education, Guangzhou 510642, China; Email: huabao@scau.edu.cn (Q.W.); huangjingfei1983@yahoo.com.cn (J.H.); yongz800@163.com (Y.Z.); dengyueye@163.com (Y.D.) Laboratory of Insect Toxicology, South China Agricultural University, Guangzhou 510642, China Author to whom correspondence should be addressed; Email: humy@scau.edu.cn; Tel.: +86-20-8528-0308; Fax: +86-20-8528-0292. 02 04 2012 04 2012 17 4 3969 3980 15 02 2012 15 03 2012 22 03 2012 © 2012 by the authors; licensee MDPI, Basel, Switzerland. 2012

This article is an open-access article distributed under the terms and conditions of the Creative Commons Attribution license (http://creativecommons.org/licenses/by/3.0/).

Based on the original structure of harmine, several novel 1,2,3,4-tetrahydro-β-carboline, β-carboline and 1-substituted-β-carboline derivatives bearing a substituted carbohydrazide group at C-3 were designed and synthesized to investigate the structure-activity relationship of their analogues. All of the compounds were characterized by infrared (IR), proton and carbon nuclear magnetic resonance (1H-NMR, 13C-NMR), and mass spectroscopy (MS). The bioassay tests showed that N'-benzylidene-1-phenyl-β-carboline-3-carbohydrazide (C25H18N4O, m.w. 390.4) (c2) and N'-(4-trifluoromethyl-benzylidene)-1-phenyl-β-carboline-3-carbohydrazide (C26H17N4OF3, m.w. 458) (d2) exhibited good inhibitory activity against dicotyledonous and monocotyledonous weeds, with EC50 values of 4.83 µM and 14.25 µM, respectively.

 N'-substituted-1,2,3,4-β-tetrahydro-β-carboline-3-carbohydrazide β-carboline N'-substituted-β-carboline-3-carbohydrazides 1-substituted-β-carboline-3-carbohydrazides herbicidal activity 1. Introduction

Harmine compounds and their structurally related compounds, belonging to the β-carboline alkaloids class, are present in medicinal plants such as Peganum harmala and Eurycoma longifolia. These compounds have recently drawn increasing interest due to their diverse biological activities, including pharmacological, neurophysiologic and biochemical activities [1,2,3,4,5,6]. Some plants which contain these compounds are used in traditional medicine in China, Brazil and other areas of the World for their emmenagogue, abortifacient, anticancer, antispasmodic and sedative effects [7,8].

As for pest management, the extracts of Peganum L. plant species containing a mixture of harmine, harmaline and norharman, as well as their derivatives, have long been proven to have insecticidal, fungicidal and plant growth regulatory properties [9,10,11,12,13,14]. Some research has revealed that P. harmala residues could cause great negative effects on seedling length, seedling dry weight, leaf area and chlorophyll content of Avena fatua L. (Poaceae) and Convolvulus arvensis L. (Convolvulaceae), showing their potential herbicidal activity [15,16], but there has been little systematic research on the effect of substituents on the pesticidal activities, therefore, the present study was designed to synthesize a series of novel β-carboline derivatives bearing a substituted carbohydrazide group at C-3, followed by their in vivo herbicidal activity evaluation.

 2. Results and Discussion 2.1. Chemistry

Previous structure-activity relationship studies had demonstrated the influence of substituents in positions-1, -3, and -9 of the β-carboline skeleton for a variety of synthetic β-carboline derivatives [17,18,19,20]. In order to study the effect of main structure and the substituent groups at position-1 and -3 on their herbicidal activity, we synthesized a series of 23 novel 1,2,3,4-tetrahydro-β-carboline and β-carboline derivatives bearing a substituted carbohydrazide group at C-3 and substituted groups at C-1 according to Love [17] (Scheme 1). According to their structural characteristics, these compounds could be divided into four series, including four N'-substituted-1,2,3,4-tetrahydro-β-carboline-3-carbohydrazides, 12 N'-substituted-β-carboline-3-carbohydrazides, four N'-benzylidene-1-substituted-β-carboline-3-carbohydrazides and three N'-substituted-benzylidene-1-substituted-β-carboline-3-carbohydrazides. All these compounds were characterized by their melting point, mass, infrared, 1H-NMR and 13C-NMR spectra that confirmed the proposed structures of the new compounds. It was also found that the Pictet-Spengler reactions of L-tryptophan with different aldehydes were different, as the reaction rates were not only related with the size of aldehydes, but also with the electronic properties of their substituents. Thus, 1,2,3,4-tetrahydro-β-carboline could be produced by the reaction of paraformaldehyde with L-tryptophan under anhydrous conditions. Benzaldehydes with an electron-withdrawing substituent reacted more easily with L-tryptophan than those bearing an electron-donating substituent. In this study, under the conditions of elevated temperature and increased pressure, condensation of tetrahydro-β-carboline and β-carboline with aromatic aldehydes in the presence of dehydrating agents under reflux in ethanol yielded the corresponding carbohydrazides. Because of the instability of tetrahydro-β-carbolines, they were hard to react with aromatic aldehydes, especially those aldehydes with electron-withdrawing substituents or high steric hindrance.

molecules-17-03969-scheme1_Scheme 1

The synthetic protocols for the target compounds.

 2.2. Herbicidal Activity

The target compounds were screened for herbicidal activities against rape and barnyard grass. The results (Table 1) indicated that these compounds showed some degree of herbicidal activities against rape, but weak activity against barnyard grass.

molecules-17-03969-t001_Table 1

Herbicidal activity of compounds (% I; concentration, μg/mL).

Compound B. campestris E. crusgalli
100 10 100 10
a1 25.31 3.75 15.04 0.00
a2 37.12 8.69 8.62 0.00
a3 33.54 5.28 23.80 2.51
a4 16.45 0.00 0.00 0.00
b1 55.63 18.13 35.94 11.83
b2 71.59 24.72 29.55 17.48
b3 58.40 16.27 37.12 15.07
b4 42.66 13.85 12.63 0.00
b5 47.32 18.02 0.00 0.00
b6 85.41 30.95 43.19 24.65
b7 50.13 19.36 47.61 18.05
b8 63.25 27.44 32.95 13.26
b9 17.85 2.59 0.00 0.00
b10 90.83 32.17 28.05 6.34
b11 23.68 7.52 0.00 0.00
b12 10.46 0.00 0.00 0.00
c1 87.05 37.22 51.47 21.85
c2 100 62.09 73.93 30.38
c3 82.35 27.12 31.16 19.35
c4 91.73 66.97 43.72 16.74
d1 76.49 35.38 35.68 9.76
d2 100 57.85 60.32 27.94
d3 93.71 66.90 57.87 24.15
harmine 53.71 20.16 32.49 10.82
2,4-D 100 — 100 100

Their herbicidal activities were determined by the core structure and the substituents at positions 1 and 3. The fully aromatic β-carbolines showed better herbicidal activities than those with tetrahydro-β-carboline moieties and the appropriate substituents at position 1 which could reinforce their activities. In this research, it was found substituted phenyls with an electron-withdrawing substituent and little steric hindrance had better activities. The substituents of position 3 could also affect the activity. An electron-withdrawing substituent or substructure with a high herbicidal activity could enhance their bioactivities. Furthermore, it was found that some seeds would not germinate after treatment with compounds at the concentration of 100 μg/mL. On the other hand, the roots of the control treated with 2,4-D (a common herbicide, Figure 1) were inhibited after germinating. According to the primary screening results, two compounds—c2 and d2—with higher activity were selected for further investigations of EC50 and probit (mortality%)-log (concentration) lines. The results are shown in Table 2.

The structural formula of harmine and 2,4-D [(2,4-dichlorophenoxy)acetic acid].

molecules-17-03969-t002_Table 2

EC50 values of compounds c2 and d2.

Compound y = a + bx EC50
c2 y = 4.4025 + 0.8710x 4.83
d2 y = 2.5709 + 2.1052x 14.25
3. Experimental 3.1. General

All reagents were purchased from commercial suppliers and dried and purified when necessary. Melting points were determined on an XT-4 binocular microscope (Beijing Tech Instrument Co., Beijing, China) and were uncorrected. 1H-NMR spectra were recorded in DMSO-d6 solutions with a Bruker AC-P500 (500 MHz) instrument, using tetramethylsilane as an internal standard. Infrared spectra were measured on an ACATAR 360 Fourier Transform Infrared Spectrometer using potassium bromide (KBr) disks, scanning from 400 to 4,000 cm−1. MS were obtained on an Agilent 6890N-5975 instrument (Agilent Technologies, Inc., Palo Alto, CA, USA). Elemental analyses (C, H and N) were carried out on an Elementar Vario EL CHNS Elemental Analyzer (Elementar, Hanau, Germany). FAB-MS spectra were obtained from VG ZAB-HS spectrometer (VG Instrument Inc., Manchester, UK). Silica gel F254 was used in analytical thin-layer chromatography (TLC) and silica gel was used in column chromatography. Yields were not optimized.

3.1.1. General Synthesis

The synthetic route for the preparation of 1,2,3,4-tetrahydro-β-carboline-3-carbohydrazide 3a and β-carboline-3-carbohydrazides 5a–e is presented in Scheme 1. Methyl tetrahydro-β-carboline-3-carboxylates 2a–e were prepared through Pictet-Spengler condensation of L-tryptophan (1) with polyoxymethylene (a), acetaldehyde (b), 3,4,5-trimethoxybenzaldehyde (c), 4-(trifluoromethyl) benzaldehyde (d), and benzaldehyde (e), in acid media, and subsequent esterification of the corresponding carboxylic acids with methanol and thionyl chloride. Oxidation of methyl 1,2,3,4-tetrahydro-β-carboline-3-carboxylates 2a–e with KMnO4 under cooled DMF, furnished methyl β-carboline-3-carboxylates 4b–e. Conversion of 2a and 4b–e to 1,2,3,4-tetrahydro-β-carboline-3-carbohydrazides 3a and β-carboline-3-carbohydrazides 5a–e was carried out by reaction with hydrazine hydrate in ethanol under reflux according to the procedures described in literature for similar compounds [21]. Condensation of 3a and 5b–e with the aromatic aldehydes 4-methoxybenzaldehyde, 4-nitrobenzaldehyde, 3,4,5-trimethoxybenzaldehyde, 2,4,6-trimethoxybenzaldehyde, 2-hydroxybenzaldehyde, 4-hydroxy-3-methoxybenzaldehyde, benzaldehyde, and 4-chlorobenzaldehyde under reflux in ethanol yielded the carbohydrazides a1–4, b1–12, c1–4 and d1–3.

General Synthesis Procedure for N'-Substituted-1,2,3,4-tetrahydro-β-carboline-3-carbohydrazides a1–4, N-Substituted-β-carboline-3-carbohydrazides b1–12, 1-Substituted-N-phenyl-β-carboline-3-carbohydrazides c1–4 and 1-Substituted-N-substituted-β-carboline-3-carbohydrazides d1–3

A solution of 3a derivatives 5b–e (1 mmol) in ethanol (15 mL) was stirred and refluxed for 10 min until complete dissolution. Then, a solution of aldehyde (1 mmol) in ethanol (3 mL) was added. Five drops of acetic acid were added as a catalyst. The mixture was refluxed for 0.5 h–4 h. Precipitates were filtered and dried, furnishing the title compounds a1–4 (b1–12, c1–4 and d1–3) in 62–90% yields.

 3.1.2. Spectral Data

N'-Benzylidene-1,2,3,4-tetrahydro-β-carboline-3-carbohydrazide (C19H18N4O, m.w. 318.4) (a1). Yield: 83.5%; m.p.: 247–249 °C; FAB-MS m/z (M+1) 319; IR (cm−1): 3409, 2923, 1675, 1625; 1H-NMR: 2.81 (1H, q, J = 12.5 Hz, C(4)H, c), 3.12 (1H, dd, J = 18 Hz, C(4)H, c), 3.62 (1H, d, J = 13.5 Hz, C(1)H, c), 3.68 (1H, dd, J = 14.5 Hz, N(2)H, c), 3.83 (1H, d, J = 14 Hz, C(1)H, c), 5.55 (1H, dd, J = 2 Hz, C(3)H, c), 6.97 (9H, m, Ph), 8.98 (1H, s, NH), 10.77 (1H, s, N(9)H, c); 13C-NMR: 25.6, 32.1, 75.2, 103.5, 109.7, 117.3, 118.8, 120.5, 126.4, 127.9, 128.7, 130.2, 132.7, 133.7, 138.4, 147.2, 160.3; Anal. Calcd for C19H18N4O: C, 71.68; H, 5.70; N, 17.60; Found: C, 71.35; H, 5.92; N, 17.53.

N'-(4-Methoxybenzylidene)-1,2,3,4-tetrahydro-β-carboline-3-carbohydrazide (C20H20N4O2, m.w. 348.4) (a2). Yield: 93%; m.p.: 258–259 °C; FAB-MS m/z (M+1) 349; IR (cm−1): 3425, 2923, 2851, 1720, 1607, 1508, 1250, 1164, 1028; 1H-NMR: 2.77 (1H, q, J = 25 Hz, C(4)H, c), 3.10 (1H, dd, J = 18 Hz, C(4)H, c), 3.61 (2H, d, J = 14 Hz, C(1)H, c), 3.80 (1H, bs, N(2)H, c), 3.83 (3H, s, Ph-OCH3), 5.45 (1H, dd, J = 2 Hz, C(3)H, c), 6.95–7.82(8H, m, Ph), 8.63(1 H, s, N=CH), 8.88 (1H, s, NH), 10.76 (1H, s, N(9)H, c); 13C-NMR: 25.8, 33.4, 55.6, 75.2, 103.5, 109.7, 115.2, 117.3, 118.8, 120.5, 126.4, 128.7, 130.2, 131.5, 133.7, 138.4, 160.1, 161.9; Anal. Calcd for C20H20N4O2: C, 68.95; H, 5.79; N, 16.08; Found: C, 68.71; H, 5.84; N, 15.96.

N'-(3,4,5-Trimethoxybenzylidene)-1,2,3,4-tetrahydro-β-carboline-3-carbohydrazide (C22H24N4O4, m.w. 408.5) (a3). Yield: 87%; m.p.: 207–209 °C; FAB-MS m/z (M+1) 409; IR (cm−1): 3375, 2964, 2919, 1697, 1584, 1458, 1327, 1128; 1H-NMR: 2.80 (1H, q, J = 25 Hz, C(4)H, c), 3.12(1H, dd, J = 17.5 Hz, C(4)H, c), 3.76 (9H, s, Ph-OCH3), 3.84 (1H, bs, N(2)H, c), 3.86 (2H, s, C(1)H, c), 5.45 (1H, dd, J = 1.5 Hz, C(3)H, c), 6.89 (6H, m, Ph), 8.66 (1H, s, N=CH), 8.93 (1H, bs, NH), 10.78 (1H, s, N(9)H, c); 13C-NMR: 26.3, 32.9, 56.4, 62.5, 74.2, 106.7, 107.5, 112.8, 120.4, 120.9, 122.1, 127.3, 128.5, 135.6, 137.2, 141.9, 148.1, 160.5, 161.8; Anal. Calcd for C22H24N4O4: C, 64.69; H, 5.92; N, 13.72; Found: C, 64.57; H, 6.01; N, 13.65.

N'-(1,2,3,4-Tetrahydro-β-carboline-3-carbonyl)-N-(4-(trifluoromethyl)phenyl)formohydrazonamide (C20H18F3N5O, 401.4) (a4). Yield: 62%; m.p.: 245–247 °C; FAB-MS m/z (M+1) 402; IR (KBr, cm−1): 3317, 2878, 1643, 1607, 1444, 1327, 1223, 1146; 1H-NMR: 2.66–2.68 (1H, q, J = 9.5 Hz, C(4)H, c), 2.78 (1H, dd, J = 18.5 Hz, C(4)H, c), 3.40 (1H, dd, J = 14 Hz, C(3)H, c), 3.86–3.90 (1H, d, J = 16 Hz, C(1)H, c), 3.94 (1H, d, J = 16.5 Hz, C(1)H, c), 4.26 (2H, bs, N(2)H, NH), 6.91–7.35 (8H, m, Ph), 9.05 (1H, s, NH), 10.68 (H, s, N(9)H, c); 13C-NMR: 25.7, 32.1, 73.9, 104.2, 112.1, 116.4, 118.2, 120.3, 121.8, 124.5, 126.1, 126.9, 128.6, 130.5, 136.2, 146.3, 148.7, 158.2; Anal. Calcd for C20H18F3N5O: C, 59.85; H, 4.52; N, 17.45; Found: C, 59.74; H, 4.68; N, 17.31.

N'-Benzylidene-β-carboline-3-carbohydrazide (C19H14N4O, m.w. 314.3) (b1). Yield: 89%; m.p.: 289–291 °C; FAB-MS m/z (M+1) 315; IR (cm−1): 3293, 1658, 1620, 1524; 1H-NMR: 7.31 (1H, t, J = 15 Hz, C(6)H, c), 7.45 (3H, m, J = 25.5 Hz, Ph(3,4,5)), 7.60 (1H, t, J = 15 Hz, C(7)H, c), 7.68 (1H, d, J = 8 Hz, C(8)H, c), 7.74 (2H, d, J = 8 Hz, PH(2,6)), 8.45 (1H, d, J = 8 Hz, C(5)H, c), 8.67 (1H, s, N=CH), 8.96 (1H, s, C(4)H, c), 8.98 (1H, s, C(1)H, c), 11.73–11.75 (1H, bs, –N(9)H, c), 12.07 (1H, s, –NH–N); 13C-NMR: 108.3, 114.6, 118.2, 120.8, 121.8, 121.9, 127.5, 128.4, 130.3, 130.5, 133.1, 135.3, 138.2, 141.4, 148.5, 161.9; Anal. Calcd for C19H14N4O: C, 72.60; H, 4.49; N, 17.82; Found: C, 72.48; H, 4.62; N, 17.69.

N'-(4-Methoxybenzylidene)-β-carboline-3-carbohydrazide (C20H16N4O2, m.w. 344.4) (b2). Yield: 84%; m.p.: 273–275 °C; FAB-MS m/z (M+1) 345; IR (cm−1): 3447, 3409, 2925, 1658, 1604, 1251; 1H-NMR: 3.82 (3H, s, Ph(4)-OCH3), 7.03 (2H, d, J = 10.5 Hz, Ph(3,5)), 7.31–7.34 (1H, t, J = 14.5 Hz, C(6)H, c), 7.60 (1H, t, J = 16 Hz, C(7)H, c), 7.68 (3H, d, J = 8.5 Hz, C(8)H, c; Ph(2,6)), 8.44 (1H, d, J = 7.5 Hz, C(5)H, c), 8.60 (1H, s, N=CH), 8.95 (1H, s, C(4)H, c), 8.96 (1H, s, C(1)H, c), 11.93 (1H, bs, –N(9)H, c), 12.01(1H, s, –NH–N); 13C-NMR: 55.8, 108.1, 113.5, 114.9, 118.4, 120.2, 121.7, 122.3, 127.6, 131.4, 133.8, 135.3, 138.1, 141.6, 149.2, 160.3, 160.9; Anal. Calcd for C20H16N4O2: C, 69.76; H, 4.68; N, 16.27; Found: C, 69.61; H, 4.86; N, 16.12.

N'-(3,4,5-Trimethoxybenzylidene)-β-carboline-3-carbohydrazide (C22H20N4O4, m.w. 404.4) (b3). Yield: 83%; m.p.: 304–306 °C; FAB-MS m/z (M+1) 405; IR (cm−1): 3430, 3239, 2922, 1661, 1619, 1532; 1H-NMR: 3.72 (3H, s, Ph(4)-OCH3), 3.86 (6H, d, J = 4.5 Hz, Ph(3,5)-OCH3), 7.03 (2H, d, J = 10.5 Hz, Ph(2,6)), 7.31 (1H, t, J = 15 Hz, C(6)H, c), 7.60 (1H, t, J = 15.5 Hz, C(7)H, c), 7.68 (1H, d, J = 8 Hz, C(5)H, c), 8.45 (1H, d, J = 7.5 Hz, C(8)H, c), 8.55 (1H, s, C(4)H, c), 8.58 (1H, s, C(1)H, c), 8.96 (1H, s, N=CH), 11.76 (1H, bs, –N(9)H, c), 12.03(1H, s, –NH–N); 13C-NMR: 56.5, 62.3, 107.2, 109.6, 114.4, 118.7, 120.4, 121.2, 121.9, 128.6, 130.1, 133.5, 134.8, 139.2, 141.6, 145.3, 148.9, 158.3, 161.7; Anal. Calcd for C22H20N4O4: C, 65.34; H, 4.98; N, 13.85; Found: C, 65.19; H, 5.24; N, 13.57.

N'-(2,4,6-Trimethoxybenzylidene)-β-carboline-3-carbohydrazide (C22H20N4O4, m.w. 404.4) (b4). Yield: 54%; m.p.: 213–215 °C; FAB-MS m/z (M+1) 405; IR (cm−1): 3268, 2920, 2854, 1669, 1605, 1227; 1H-NMR: 3.82 (6H, s, Ph(2,6)-OCH3), 3.84 (3H, s, Ph(4)-OCH3), 6.30 (2H, s, Ph(3,5)), 7.30 (1H, t, J = 15 Hz, C(6)H, c), 7.59 (1H, t, J = 15.5 Hz, C(7)H, c), 7.67 (1H, d, J = 8 Hz, C(5)H, c), 8.43 (1H, d, J = 8 Hz, C(8)H, c), 8.63 (1H, s, C(4)H, c), 8.90 (1H, s, C(1)H, c), 8.93 (1H, s, N=CH), 11.69 (1H, bs, –N(9)H, c), 11.98(1H, s, –NH–N); 13C-NMR: 55.7, 55.9, 95.2, 105.4, 108.6, 112.5, 118.3, 120.7, 121.6, 123.1, 127.9, 134.5, 134.8, 139.5, 141.2, 145.3, 148.9, 160.1, 161.5; Anal. Calcd for C22H20N4O4: C, 65.34; H, 4.98; N, 13.85; Found: C, 65.21; H, 5.19; N, 13.61.

N'-(4-Chlorobenzylidene)-β-carboline-3-carbohydrazide (C19H13ClN4O, m.w. 348.8) (b5). Yield: 93%; m.p.: 269–271 °C; FAB-MS m/z (M+1) 349; IR (cm−1): 3272, 1679, 1626, 1494; 1H-NMR: 7.31 (1H, t, J = 15 Hz, C(6)H, c), 7.53 (2H, d, J = 8.5 Hz, Ph(3,5)), 7.60 (1H, t, J = 16 Hz, C(7)H, c), 7.68 (1H, d, J = 8 Hz, C(5)H, c), 7.75 (2H, d, J = 8.5 Hz, Ph(2,6)), 8.45 (1H, d, J = 8 Hz, C(8)H, c), 8.67 (1H, s, C(4)H, c), 8.96 (1H, s, C(1)H, c), 8.98 (1H, s, N=CH), 11.762 (1H, bs, –N(9)H, c), 12.03(1H, s, –NH–N); 13C-NMR: 109.2, 113.8, 118.6, 121.1, 121.9, 123.1, 127.9, 130.4, 131.7, 134.1, 134.6, 137.8, 138.3, 139.5, 145.3, 148.9, 160.1; Anal. Calcd for C19H13ClN4O: C, 65.43; H, 3.76; N, 16.06; Found: C, 65.28; H, 3.95; N, 15.87.

N'-(4-Nitrobenzylidene)-β-carboline-3-carbohydrazide (C19H13N5O3, m.w. 359.3) (b6). Yield: 92%; m.p.: >300 °C; FAB-MS m/z (M+1) 360; IR (cm−1): 3446, 3230, 1684, 1627, 1518; 1H-NMR: 7.32 (1H, t, J = 15.5 Hz, C(6)H, c), 7.61 (1H, t, J = 15 Hz, C(7)H, c), 7.68 (1H, d, J = 8.5 Hz, C(5)H, c), 7.99 (2H, d, J = 8.5 Hz, Ph(2,6)), 8.32 (2H, d, J = 9 Hz, Ph(3,5)), 8.46 (1H, d, J = 8 Hz, C(8)H, c), 8.79 (1H, s, C(4)H, c), 8.97 (1H, s, C(1)H, c), 9.00 (1H, s, N=CH), 12.04 (1H, bs, –N(9)H, c), 12.40 (1H, s, –NH–N); 13C-NMR: 108.7, 114.1, 119.2, 120.6, 121.3, 123.7, 128.2, 134.2, 134.7, 134.6, 137.8, 139.5, 141.7, 145.4, 147.6, 158.3, 161.2; Anal. Calcd for C19H13N5O3: C, 63.51; H, 3.65; N, 19.49; Found: C, 63.36; H, 3.83; N, 19.21.

N'-(2-Hydroxybenzylidene)-β-carboline-3-carbohydrazide (C19H14N4O2, m.w. 330.3) (b7). Yield: 83%; m.p.: 283–285 °C; FAB-MS m/z (M+1) 331; IR (cm−1): 3457, 3254, 1663, 1620, 1493, 1351; 1H-NMR: 6.93 (2H, q, J = 10.5 Hz, Ph(3,5)), 7.30 (2H, m, J = 23.5 Hz, C(6)H, c; Ph(4)), 7.46 (1H, d, J = 7.5 Hz, C(5)H, c), 7.59 (1H, m, J = 32 Hz, Ph(6)), 7.69 (1H, t, J = 8.5 Hz, C(7)H, c), 8.44 (1H, d, J = 7.5 Hz, C(8)H, c), 8.85 (1H, s, C(4)H, c), 8.97 (1H, s, C(1)H, c), 8.98 (1H, s, N=CH), 11.62 (1H, bs, –N(9)H, c), 12.05(1H, s, –NH–N), 12.45 (1H, s, Ph-OH); 13C-NMR: 108.6, 114.3, 118.9, 120.1, 120.4, 120.9, 121.5, 123.8, 125.3, 127.6, 134.2, 135.1, 135.7, 138.3, 139.6, 145.2, 147.8, 160.3, 160.7; Anal. Calcd for C19H14N4O2: C, 69.08; H, 4.27; N, 16.96; Found: C, 68.94; H, 4.58; N, 16.72.

N'-(4-Hydroxy-3-methoxybenzylidene)-β-carboline-3-carbohydrazide (C20H16N4O3, m.w. 360.4) (b8). Yield: 83%; m.p.: 163–165 °C; FAB-MS m/z (M+1) 361; IR (cm−1): 3430, 2924, 1663, 1600, 1505, 1380, 1278; 1H-NMR: 3.85 (3H, s, Ph(4)-OCH3), 6.85 (1H, d, J = 8 Hz, Ph(5)), 7.08 (1H, t, J = 16.5 Hz, C(6)H, c), 7.31 (2H, m, J = 18 Hz, Ph(2,6)), 7.60 (1H, d, J = 23.5 Hz, C(5)H, c), 7.67 (1H, t, J = 8 Hz, C(7)H, c), 8.44 (1H, d, J = 7.5 Hz, C(8)H, c), 8.54 (1H, s, C(4)H, c), 8.94 (1H, s, C(1)H, c), 8.95 (1H, s, N=CH), 9.54 (1H, bs, Ph-OH), 11.74 (1H, bs, –N(9)H, c), 12.01 (1H, s, –NH–N); 13C-NMR: 56.4, 109.2, 114.1, 114.8, 119.2, 119.9, 120.6, 122.1, 123.5, 126.7, 128.3, 131.9, 135.4, 138.3, 139.6, 145.2, 147.6, 148.1, 150.8, 160.3; Anal. Calcd for C20H16N4O3: C, 66.66; H, 4.48; N, 15.55; Found: C, 66.38; H, 4.65; N, 15.29.

N'-(Furan-2-ylmethylene)-β-carboline-3-carbohydrazide (C17H12N4O2, m.w. 304.3) (b9). Yield: 61%; m.p.: >300 °C; FAB-MS m/z (M+1) 305; IR (cm−1): 3284, 1658, 1622; 1H-NMR: 6.64 (1H, t, J = 3 Hz, furan(4)), 6.90 (1H, d, J = 3.5 Hz, furan(3)), 7.30 (1H, t, J = 15 Hz, C(6)H, c), 7.61 (1H, d, J = 8 Hz, furan(5)), 7.67 (1H, t, J = 8 Hz, C(7)H, c), 7.86 (1H, s, C(4)H, c), 8.44 (1H, d, J = 8 Hz, C(8)H, c), 8.58 (1H, s, C(1)H, c), 8.95 (1H, d, J = 5 Hz, C(5)H, c), 8.97 (1H, s, N=CH), 11.74 (1H, d, J = 15 Hz, –N(9)H, c), 12.02 (1H, s, ‑NH–N); 13C-NMR: 108.7, 114.5, 115.8, 118.4, 119.3, 120.6, 122.1, 123.5, 128.3, 135.4, 137.6, 138.6, 139.6, 145.5, 148.3, 150.8, 160.4; Anal. Calcd for C17H12N4O2: C, 67.10; H, 3.97; N, 18.41; Found: C, 66.85; H, 4.18; N, 18.27.

N'-((5-Chloro-3-methyl-1H-pyrazol-4-yl)methylene)-β-carboline-3-carbohydrazide (C17H13ClN6O, m.w. 352.8) (b10). Yield: 74%; m.p.: 259–261 °C; FAB-MS m/z (M+1) 353; IR (cm−1): 3430, 3239, 2922, 1661, 1619, 1532; 1H-NMR: 2.50 (3H, s, pyrazole-CH3), 7.31 (1H, q, J = 15 Hz, C(6)H, c), 7.60 (1H, dd, J = 19.5 Hz, C(7)H, c), 7.67 (1H, d, J = 8 Hz, C(5)H, c), 8.43 (1H, d, J = 7.5 Hz, C(8)H, c), 8.57 (1H, s, N=CH), 8.91 (1H, s, C(4)H, c), 8.94 (1H, s, C(1)H, c), 11.69–11.71 (1H, bs, –N(9)H, c), 11.96 (1H, s, –NH–N), 13.18 (1H, bs, NH, pyrazole); 13C-NMR: 15.7, 107.2, 112.1, 112.8, 117.5, 119.6, 120.1, 124.7, 128.3, 134.6, 138.3, 138.6, 144.2, 145.6, 148.3, 149.8, 161.2; Anal. Calcd for C17H13ClN6O: C, 57.88; H, 3.71; N, 23.82; Found: C, 57.63; H, 3.96; N, 23.68.

N'-(β-Carboline-3-carbonyl)-N-(4-(trifluoromethyl)phenyl)formohydrazonamide (C20H13F3N4O, m.w. 382.3) (b11). Yield: 85%; m.p.: 248–250 °C; FAB-MS m/z (M+1) 398; IR (cm−1): 3248, 3222, 1647, 1617, 1337; 1H-NMR: 4.58 (1H, bs, N=C–NH), 6.92–7.02 (2H, m, Ph(2,6)), 7.20 (1H, q, J = 10 Hz, C(6)H, c), 7.30 (1H, d, J = 8 Hz, C(5)H, c), 7.39 (1H, dd, J = 10 Hz, C(7)H, c), 7.56 (3H, m, N=CH; Ph(3,5)), 8.38 (1H, d, J = 15 Hz, C(8)H, c), 8.81 (1H, s, C(4)H, c), 8.88 (1H, s, C(1)H, c), 11.64 (1H, bs, –N(9)H, c), 11.97 (1H, s, ‑NH–N); 13C-NMR: 109.6, 112.8, 117.5, 118.3, 119.6, 121.5, 124.5, 128.4, 128.9, 130.2, 131.8, 134.4, 134.8, 144.2, 147.6, 148.2, 150.3, 160.7; Anal. Calcd for C20H13F3N4O: C, 60.45; H, 3.55; N, 17.62; Found: C, 60.27; H, 3.74; N, 17.39.

N'-(Diphenylmethylene)-β-carboline-3-carbohydrazide (C25H18N4O, m.w. 390.4) (b12). Yield: 70%; m.p.: >300 °C; FAB-MS m/z (M+1) 391; IR (cm−1): 3257, 3175, 1667, 1624, 1495, 1254; 1H-NMR: 7.31 (1H, t, J = 10 Hz, C(6)H, c), 7.43 (5H, m, Ph1(2,3,4,5,6)), 7.60 (5H, m, Ph2(2,3,4,5,6)), 7.64 (1H, d, J = 8.5 Hz, C(5)H, c), 7.71 (1H, t, J = 10.5 Hz, C(7)H, c), 8.43 (1H, d, J = 7.5 Hz, C(8)H, c), 8.64 (1H, s, C(4)H, c), 8.96 (1H, s, C(1)H, c), 11.03 (1H, bs, –N(9)H, c), 12.04(1H, s, –NH–N); 13C-NMR: 108.4, 115.7, 118.1, 120.6, 121.4, 124.7, 128.3, 128.8, 131.2, 133.7, 134.1, 134.9, 138.3, 145.6, 148.6, 160.2, 160.8; Anal. Calcd for C25H18N4O: C, 76.91; H, 4.65; N, 14.35; Found: C, 76.68; H, 4.82; N, 14.16.

N'-Benzylidene-1-methyl-β-carboline-3-carbohydrazide (C20H16N4O, m.w. 328.4) (c1). Yield: 63%; m.p.: >300 °C; FAB-MS m/z (M+1) 329; IR (cm−1): 3275, 2921, 1667, 1623, 1523; 1H-NMR: 2.91 (3H, s, –CH3), 7.30 (1H, m, J = 16.2 Hz, C(6)H, c), 7.45 (1H, m, J = 8.4 Hz, C(7)H, c), 7.48 (2H, m, J = 14.4 Hz, C(3,5)H, Ph), 7.59 (1H, m, J = 16.2 Hz, C(4)H, Ph), 7.66 (1H, m, J = 8.4 Hz, C(8)H, c), 7.76 (2H, d, J = 8.4 Hz, C(2,6)H, Ph), 8.40 (1H, d, J = 7.8 Hz, C(5)H, c), 8.68 (1H, s, C(4)H, c), 8.80 (1H, s, –N=CH), 11.83 (1H, s, –NH, c), 12.03 (1H, s, –NH–N); 13C-NMR: 14.8, 111.5, 114.7, 119.6, 120.1, 124.7, 125.3, 128.8, 129.7, 134.2, 138.5, 139.6, 144.2, 145.6, 147.3, 148.7, 150.3, 159.8; Anal. Calcd for C20H16N4O: C, 73.15; H, 4.91; N, 17.06; Found: C, 72.98; H, 5.06; N, 16.85.

N'-Benzylidene-1-phenyl-β-carboline-3-carbohydrazide (C25H18N4O, m.w. 390.4) (c2). Yield: 87%; m.p.: 271–273 °C; FAB-MS m/z (M+1) 391; IR (cm−1): 3281, 3200, 1667, 1624, 1518; 1H-NMR: 7.37 (1H, m, J = 15.6 Hz, C(6)H, c), 7.46 (1H, m, J = 15.6 Hz, C(4)H, Ph1), 7.48 (2H, m, J = 15.6 Hz, C(3,5)H, Ph1), 7.60 (1H, m, J = 10.2 Hz, C(7)H, c), 7.62 (1H, m, J = 10.2 Hz, C(8)H, c), 7.70 (3H, m, J = 28.2 Hz, C(3,4,5)H, Ph2), 7.78 (2H, t, J = 8.4 Hz, C(2,6)H, Ph1), 8.22 (2H, m, J = 8.4 Hz, C(2,6)H, Ph2), 8.48 (1H, d, J = 7.8 Hz, C(4)H, c), 8.68 (1H, s, C(5)H, c), 8.97 (1H, s, –N = CH), 11.81 (1H, s, –NH, c), 11.93 (1H, s, –NH–N); 13C-NMR: 111.3, 116.1, 119.7, 121.4, 123.9, 126.5, 128.7, 128.9, 129.2, 129.5, 130.2, 130.8, 131.6, 132.1, 134.8, 136.5, 139.2, 142.7, 143.2, 149.3, 161.8; Anal. Calcd for C25H18N4O: C, 76.91; H, 4.65; N, 14.35; Found: C, 76.72; H, 4.84; N, 14.19.

N'-Benzylidene-1-(4-(trifluoromethyl)phenyl)-β-carboline-3-carbohydrazide (C26H17F3N4O, m.w. 458.4) (c3). Yield: 80.5%; m.p.: 235–237 °C; FAB-MS m/z (M+1) 459; IR (cm−1): 3436, 1730, 1622, 1325; 1H-NMR: 7.35–8.43 (13H, Ph1, Ph2, c), 8.67 (1H, s, C(4)H, c), 9.02 (1H, s, –N=CH), 11.87 (1H, s, –NH, c), 12.07 (1H, s, –NH–N); 13C-NMR: 112.5, 115.7, 120.1, 121.3, 122.9, 124.3, 127.3, 128.8, 129.1, 130.5, 131.2, 131.8, 134.7, 135.6, 138.5, 139.6, 141.6, 144.2, 147.3, 148.7, 160.8; Anal. Calcd for C26H17F3N4O: C, 68.12; H, 3.74; N, 12.22; Found: C, 67.94; H, 3.97; N, 12.08.

N'-Benzylidene-1-(4-chlorophenyl)-β-carboline-3-carbohydrazide (C25H17ClN4O, m.w. 424.9) (c4). Yield: 86%; m.p.: 220–221 °C; FAB-MS m/z (M+1) 425; IR (cm−1): 3419, 1683, 1624, 1511, 1351; 1H-NMR: 7.34 (1H, q, J = 15.6 Hz, C(6)H, c), 7.46 (3H, m, J = 30.6 Hz, C(3,4,5)H, Ph2), 7.62 (1H, m, J = 16.2 Hz, C(7)H, c), 7.70 (1H, d, J = 8.4 Hz, C(8)H, c), 7.73 (2H, d, J = 15.6 Hz, C(3,5)H, Ph1), 7.77 (2H, m, J = 8.4 Hz, C(2,6)H，Ph2), 8.26 (2H, d, J = 9 Hz, C(2,6)H, Ph1), 8.48 (1H, d, J = 8.4 Hz, C(5)H, c), 8.68 (1H, s, C(4)H, c), 8.98 (1H, s, –N=CH), 11.83 (1H, s, –NH, c), 11.97 (1H, s, –NH–N); 13C-NMR: 112.7, 114.9, 120.3, 121.6, 122.9, 124.3, 128.1, 129.4, 130.5, 131.7, 132.8, 134.2, 135.6, 138.5, 139.6, 141.6, 144.8, 148.1, 148.5, 160.3; Anal. Calcd for C25H17ClN4O: C, 70.67; H, 4.03; N, 13.19; Found: C, 70.42; H, 4.29; N, 13.05.

N'-(4-Trifluoromethylbenzylidene)-1-(4-trifluoromethyl-phenyl)-β-carboline-3-carbohydrazide) (C27H16F6N4O, m.w. 526.4) (d1). Yield: 83.9%, m.p.: 289–290 °C; FAB-MS m/z (M+1) 527; IR (cm−1): 3438, 1735, 1658, 1381; 1H-NMR: 7.34–8.48 (12H, Ph1, Ph2, c), 8.75 (1H, s, C(4)H, c), 8.99 (1H, s, –N=CH), 12.02 (1H, s, –NH, c), 12.09 (1H, s, –NH–N); 13C-NMR: 112.7, 114.7, 120.3, 121.5, 122.9, 124.3, 127.3, 128.8, 129.1, 131.2, 132.7, 138.5, 144.6, 147.3, 148.5, 149.2, 150.9, 161.8; Anal. Calcd for C27H16F6N4O: C, 61.60; H, 3.06; N, 10.64; Found: C, 61.38; H, 3.24; N, 10.47.

N'-(4-Trifluoromethylbenzylidene)-1-phenyl-β-carboline-3-carbohydrazide (C26H17N4OF3, m.w. 458.4) (d2). Yield: 86.6%, m.p.: 235–237 °C; FAB-MS m/z (M+1) 459; IR (cm−1): 3379, 1723, 1594, 1487, 1364; 1H-NMR: 7.33–8.76 (13H, Ph1, Ph2, c), 8.98 (1H, s, C(4)H, c), 9.00 (1H, s, –N=CH), 11.98 (1H, s, –NH, c), 11.99 (1H, s, –NH–N); 13C-NMR: 112.5, 114.9, 120.4, 121.8, 122.5, 125.2, 127.3, 128.1, 129.3, 130.5, 131.2, 131.8, 134.7, 135.6, 138.5, 139.6, 142.6, 145.2, 148.3, 148.5, 160.2; Anal. Calcd for C26H17F3N4O: C, 68.12; H, 3.74; N, 12.22; Found: C, 67.96; H, 3.97; N, 12.11.

N'-(4-Trifluoromethylbenzylidene)-1-(4-chlorophenyl)-β-carboline-3-carbohydrazide (C26H16ClN4OF3, m.w. 492.9) (d3). Yield: 88.8%, m.p.: 140–142 °C; FAB-MS m/z (M+1) 493; IR (cm−1): 3427, 1692, 1583, 1491; 1H-NMR: 7.36–8.76 (12H, Ph1, Ph2, c), 8.76 (1H, s, C(4)H, c), 8.99 (1H, s, –N=CH), 12.02 (1H, s, –NH, c), 12.03 (1H, s, –NH–N); 13C-NMR: 112.7, 115.1, 120.6, 121.5, 121.9, 124.7, 127.2, 128.4, 129.5, 132.2, 132.7, 138.5, 144.6, 147.3, 148.2, 148.9, 150.4, 160.6; Anal. Calcd for C26H16ClF3N4O: C, 63.36; H, 3.27; N, 11.37; Found: C, 63.19; H, 3.45; N, 11.24.

 3.2. Biological Assays

All compounds were formulated as 10 g/L emulsified concentrates using DMSO as solvent and TW-80 as emulsification reagent. The stock solutions were diluted with water to the required concentration and applied to pot-grown plants in a greenhouse at 23 ± 1 °C, 60 ± 5% relative humidity (RH), 10 flux light intensity and 8 h/day photoperiod. Twenty seeds of each weed species including Chinese cabbage (rape, Brassica campestris L. ssp.) and barnyard grass (Echinochloa crusgalli) were chosen for testing. Seedlings were grown in the test plate of 9-cm diameter containing two pieces of filter paper and 9 mL solution of the tested compound (100 mg/L and 10 mg/L, respectively). Distilled water and 2,4-D were used as the comparison compounds. The herbicidal activity was assessed by the inhibitory rate in comparison with the distilled water. The heights of the above-ground parts of the seedlings, their root lengths and fresh weights in each cup were measured, and the means were calculated. The percentage inhibition was used to describe the control efficiency of the compounds. Range from 0 to 100%, 0% means no effect and 100% means inhibition. The test was repeated three times; means were calculated and shown as activity in Table 1. The compounds with higher activity were selected for further investigations of EC50 and probit (mortality%)-log (concentration) lines, which are shown in Table 2.

 4. Conclusions

New 1,2,3,4-tetrahydro-β-carboline, β-carboline and 1-substituted-β-carboline derivatives bearing a substituted carbohydrazide group at C-3 were designed and synthesized to study the structure-activity relationships of their analogues. The results showed that some of the newly synthesized carbohydrazide derivatives carrying phenyl groups substituted with an electron-withdrawing substituent could be used for the further development of novel herbicides.

Acknowledgments

The present study was supported by grants from the China National Nature Science Foundation (31171870) and China National Nature Science Foundation (31171882).

 References and Notes Carbrera G.M. Seldes A.M. A β-carboline alkaloid from the soft coral lignopsis spongiosum J. Nat. Prod. 1999 62 759 760 10.1021/np980429s10346963 Glennon R.A. Dukat M. Brella B. Hong S.S. Constantino L. Teitler M. Smith C. Egan C. Davis K. Mattson M.V. Binding of β-carbolines and related agents at serotonin (5-HT2 and 5-HT1A), dopamine (D2) and benzodiazepines receptors Drug Alcohol Depend. 2000 60 121 132 10.1016/S0376-8716(99)00148-910940539 Kotanen S. Huybrechts J. Cerstiaens A. Zoltan K. Daloze D. Baggerman G. Forgo P. Loof A.D. Schoofs L. Identification of tryptophan and beta-carboline as paralysins in larvae of the yellow mealworm, Tenebrio molitor Biochem. Biophys. Res. Commun. 2003 310 64 71 10.1016/j.bbrc.2003.08.121 Song X.H. Liu X.H. Lin Y.C. Metabolites of mangrove fungus NO.K23 and interaction of carboline with DNA (in Chinese) Chin. J. Trop. Oceanogr. 2004 23 66 70 Herraiz T. Chaparro C. Analysis of monoamine oxidase enzymatic activity by reversed-phase high performance liquid chromatography and inhibition by β-carboline alkaloids occurring in foods and plants J. Chromatogr. A 2006 1120 237 243 10.1016/j.chroma.2005.12.009 Herraiz T. Chaparro C. Human monoamine oxidase enzyme inhibition by coffee and β-carbolines norharman and harman isolated from coffee Life Sci. 2006 78 795 802 10.1016/j.lfs.2005.05.07416139309 Sun D.J. Lee Y. Advance in Peganum multisectum and main active component of norharman (in Chinese) J. Xinjiang Med. Univ. 2003 26 125 128 Cao R.H. Peng W.L. Wang Z.H. Xu A.L. β-Carboline alkaloids: Biochemical and pharmacological functions Curr. Med. Chem. 2007 14 479 500 10.2174/092986707779940998 Liu J.X. Zhao G.L. Effects of substance extracted from Peganum Multisectum Maxim Bobr on growth of maize (in Chinese) Acta Bot. Boreal.-Occident. Sin. 2004 23 2200 2203 Yao W.Q. Wang J.R. Zhang P.Z. Peng J.Y. Zhang Y.Y. Insecticidal activity of alcohol extracts from Peganum harmala (in Chinese) Acta Bot. Boreal.-Occident. Sin. 2004 24 1096 1099 Weng Q.F. Zhong G.H. Hu M.Y. Luo J.J. Bioactivities and physiological effects of extracts of Peganum harmala against Bursaphelenchus xylophilus (in Chinese) Sci. Agric. Sin. 2005 38 2014 2022 Zhao X.M. Zeng Z.H. The research of the pesticidal activity on different Peganum harmala extractions (in Chinese) Chin. Agric. Sci. Bull. 2005 21 278 279 Weng Q.F. Zhong G.H. Wang W.X. Luo J.J. Hu M.Y. Effectiveness of plant extracts for the control of Meloidogyne incognita (in Chinese) J. South Chin. Agric. Univ. 2006 27 55 60 Liu J.X. Hu H.B. Zhao G.L. Effects of alkaloid of Peganum multisectum Bobr on seed germination of Cucumber (Cucumis sativus L.) Plant Physiol. Commun (in Chinese) 2007 43 250 254 Sodaeizadeh H. Rafieiolhossaini M. Havlík J. van Damme P. Allelopathic activity of different plant parts of Peganum harmala L. and identification of their growth inhibitors substances Plant Growth Regul. 2009 59 227 236 10.1007/s10725-009-9408-6 Sodaeizadeh H. Rafieiolhossaini M. van Damme P. Herbicidal activity of a medicinal plant, Peganum harmala L., and decomposition dynamics of its phytotoxins in the soil Ind. Crops Prod. 2010 31 385 394 10.1016/j.indcrop.2009.12.006 Love B.E. Synthesis of β-carbolines. A review Org. Prep. Proced. Int. 1996 28 1 64 10.1080/00304949609355907 Silverman B.D. Daniel E.P. Mike P. Isidore R. Comparative molecular moment analysis (CoMMA) Perspect. Drug Discov. Des. 1998 12-14 183 196 10.1023/A:1017046424785 Guan H.J. Chen H.S. Peng W.L. Ma Y. Cao R.H. Liu X.D. Xu A.L. Design of β-carboline derivatives as DNA-targeting antitumor agents Eur. J. Med. Chem. 2006 41 1167 1179 10.1016/j.ejmech.2006.05.00416790297 Cao R.H. Guan X.D. Shi B.X. Chen Z.Y. Ren Z.H. Peng W.L. Song H.C. Design, synthesis and 3D-QSAR of β-carboline derivatives as potent antitumor agents Eur. J. Med. Chem. 2010 45 2503 2515 10.1016/j.ejmech.2010.02.03620304536 Formagio A.S.N. Santos P.R. Zanoli K. Ueda-Nakamura T. Tonin L.T.D. Nakamura C.V. Sarragiotto M.H. Synthesis and antiviral activity of beta-carboline derivatives bearing a substituted carbohydrazide at C-3 against poliovirus and herpes simplex virus (HSV-1) Eur. J. Med. Chem. 2009 44 4695 4701 10.1016/j.ejmech.2009.07.00519647908

Sample Availability: Samples of all the compounds are available from the authors.