Synthesis and Herbicidal Activity Evaluation of Novel β-Carboline Derivatives

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.


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.

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. 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 EC 50 and probit (mortality%)-log (concentration) lines. The results are shown in Table 2.

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. 1 H-NMR spectra were recorded in DMSO-d 6 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.

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.