Abstract
To discover a novel lead structure for antiphytopathogenic fungus agent, a series of (R)-2-phenyl-4,5-dihydrothiazole-4-carboxamide derivatives containing a sulfonohydrazide moiety were designed and synthesized. They were determined by melting points, 1H NMR, 13C NMR, and elemental analysis (EA). The biological activity results revealed that these title compounds possessed antifungal and insecticidal activities. Some title compounds against Alternaria solani, Physalospora piricola, Cercospora arachidicola, Phytophthora capsici, Fusarium graminearum, and Sclerotinia sclerotiorum displayed moderate to good antifungal activities at 50 mg/L, especially, compounds 6b and 6p displayed good and broad-spectrum antifungal activities. The structure activity relationships were discussed. A 3D-QSAR model was established based on the antifungal activity against Phytophthora capsici, indicating that electrostatic and hydrophobic fields were the two most significant factors for antifungal activity. Hence, structure optimization based on the CoMSIA model was performed to find compound 6p with excellent activity against Phytophthora capsici, and the EC50 values of compound 6p were comparable to those of chlorothalonil. Furthermore, the insecticidal activity of compound 6p against Culex pipiens larvae at 1 mg/L was considerable to that of chlorantraniliprole. Therefore, compound 6p can be used as a novel lead structure for antiphytopathogenic fungus and insecticidal agent development.
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Introduction
The global population is expected to increase to over 9 billion by 2050, with the associated demand for increasing food production (Godfray et al. 2010; Ray et al. 2013). Plant diseases mainly caused by fungi, viruses, oomycetes, and bacteria have brought about severe losses to crops yield per year in the world, hence some efficient measures have been taken to resolve the issue of plant disease. It is well known that the application of agrochemicals plays a significant role in increasing the yield of crops. However, due to the widespread and frequent use of conventional agrochemicals with the same mechanism of action, the increasing resistance to agrochemicals has been a major problem in plant diseases control (Tabashnik et al. 2014; Forgash 1984). Therefore, to develop novel agrochemicals with novel mechanisms of action and eco-friendly characteristics has been an urgent task for scientists.
Natural products possess the characteristics of low toxicity, good biodegradability, and compatibility, so they have been widely used as commercial fungicides (Ma et al. 2013; Li et al. 2018), insecticides (Crouse et al. 2018; Tacoli et al. 2018), and herbicides (Duke et al. 2010). In the past years, many 2-aryl-4,5-dihydrothiazole-4-carboxylic acid derivatives with various biological and medicinal activities, including anti-HIV (Pattenden and Thom 1993), antibiotic (Zamri et al. 2003), and anticancer activity (Gududuru et al. 2005), have reported, whereas there is few report about the utilization in preventing plant disease. Recently, our research group have reported some (R)-2-aryl-4,5-dihydrothiazole-4-carboxylic acid derivatives with amide and ester moieties, which exhibited good and broad-spectrum antifungal activities (Fig. 1) (Liu et al. 2019, 2015). Sulfonyl hydrazine can act on many enzymes in organism to a variety of biological activities, such as antiviral (Selvakumar et al. 2017), antifungal (Dixit et al. 2010), antimicrobial (Siddiqa et al. 2014), antitumor (Kamal et al. 2007), and antioxidant activity (Ardjani and Mekelleche 2017).
Taking consideration of the above viewpoints, a series of (R)-2-phenyl-4,5-dihydrothiazole-4-carboxamide derivative containing a sulfonohydrazide moiety were designed and synthesized, and their antifungal and insecticidal activities were tested accordingly. The preliminary structure activity relationship (SAR) was investigated as well.
Materials and methods
1H NMR and 13C NMR were recorded on a Bruker AV400 spectrometer (400 MHz) using CDCl3 or DMSO-d6 as solvent. Chemical shift values (δ) were reported in ppm with tetramethylsilane as the internal standard. Melting points were determined on an X-4 binocular microscope melting point apparatus (Beijing Tech Instruments Co., Beijing, China) and uncorrected. Elemental analyses were performed on a Vario EL elemental analyzer. (Elementar Co., Germany). Column chromatography purification was carried out using silica gel (200–300 mesh). Reagents were all analytically or chemically pure. All solvents were dried by standard methods in advance and distilled before use. Intermediates 3a–c and 5a–e were synthesized in Scheme 1 according to the literatures (Liu et al. 2015; Backes et al. 2015).
Synthetic route of title compounds
General synthetic procedure for title compounds 6a–p
1-Hydroxy-1H-benzotriazole (HOBt, 0.072 g, 0.53 mmol), N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (EDCI, 0.115 g, 0.6 mmol) and (R)-2-phenyl-4,5-dihydrothiazole-4-carboxylic acid 3 (0.5 mmol) were subsequently added to anhydrous dichloromethane (15 mL) at 0 °C. After stirred at room temperature for 0.5 h, benzenesulfonohydrazides 5 (0.5 mmol) and N,N-diisopropylethylamine (DIPEA) (0.142 g, 1.1 mmol) were subsequently added at 0 °C. The reaction was warmed to room temperature and stirred for 4 h, and then solvent was removed under reduced pressure to give the title compounds 6a–p.
(R)-N′-(2-Phenyl-4,5-dihydrothiazole-4-carbonyl)benzenesulfonohydrazide (6a)
White solid, yield 56.1%, mp 185–186 °C (EtOAc). \([\alpha]_{\rm{D}}^{20}\) = +16.2 (c 1, MeOH). 1H NMR spectrum (400 MHz, DMSO-d6), δ, ppm (J, Hz): 10.50 (1H, s, NH), 10.18 (1H, s, NH), 7.90–7.88 (4H, m, Ph-H), 7.57 (2H, dd, J = 7.0 Hz and J = 7.2 Hz, Ph-H), 7.53 (2H, d, J = 7.5 Hz, Ph-H), 7.50 (2H, d, J = 7.7 Hz, Ph-H), 5.38 (1H, t, J = 9.1 Hz, CH), 3.79 (1H, dd, J = 10.9 Hz, J = 9.6 Hz, 1/2CH2), 3.63 (1H, dd, J = 10.9 Hz, J = 8.5 Hz, 1/2CH2). 13C NMR spectrum, δ, ppm (J, Hz): 169.59, 168.68, 132.50, 132.40, 131.92, 128.86, 128.57, 128.44, 127.50, 126.64, 78.19, 35.01. Elem. anal. calcd. for C16H15N3O3S2 (%): C 53.17; H 4.18; N, 11.63. Found (%): C 53.19; H 4.22; N 11.67.
(R)-4-Chloro-N′-(2-phenyl-4,5-dihydrothiazole-4-carbonyl)benzenesulfonohydrazide (6b)
White solid, yield 66.2%, mp 193–194 °C (EtOAc). \([\alpha]_{\rm{D}}^{20}\) = +14.1 (c 1, MeOH). 1H NMR spectrum (400 MHz, DMSO-d6), δ, ppm (J, Hz): 10.47 (1H, s, NH), 10.15 (1H, s, NH), 7.88 (2H, d, J = 7.4 Hz, Ph-H), 7.82 (2H, d, J = 8.0 Hz, Ph-H), 7.72 (2H, d, J = 7.6 Hz, Ph-H), 7.56 (1H, t, J = 7.5 Hz, Ph-H), 7.49 (2H, t, J = 7.4 Hz, Ph-H), 5.37 (1H, t, J = 8.7 Hz, CH), 3.80 (1H, dd, J = 11.0 Hz, J = 9.6 Hz, 1/2CH2), 3.64 (1H, dd, J = 10.9 Hz, J = 8.7 Hz, 1/2CH2). 13C NMR spectrum, δ, ppm (J, Hz): 169.72, 168.01, 132.77, 132.20, 131.81, 130.63, 128.86, 127.85, 127.78, 125.84, 78.50, 35.62. Elem. anal. calcd. for C16H14ClN3O3S2 (%): C 48.54; H 3.56; N 10.61. Found (%): C 48.58; H 3.59; N 10.66.
(R)-4-Methyl-N′-(2-phenyl-4,5-dihydrothiazole-4-carbonyl)benzenesulfonohydrazide (6c)
White solid, yield 57.2%, m. p. 182–183 °C (EtOAc). \([\alpha]_{\rm{D}}^{20}\) = +14.7 (c 1, MeOH) 1H NMR spectrum (400 MHz, DMSO-d6), δ, ppm (J, Hz): 10.48 (1H, s, NH), 10.15 (1H, s, NH), 7.88 (2H, d, J = 7.5 Hz, Ph-H), 7.77 (2H, d, J = 8.1 Hz, Ph-H), 7.57 (1H, t, J = 7.5 Hz, Ph-H), 7.49 (2H, t, J = 7.4 Hz, Ph-H), 7.31 (2H, d, J = 8.0 Hz, Ph-H), 5.34 (1H, t, J = 9.0 Hz, CH), 3.75 (1H, dd, J = 10.8 Hz, J = 9.6 Hz, 1/2CH2), 3.59 (1H, dd, J = 10.9 Hz, J = 8.7 Hz, 1/2CH2), 2.36 (3H, s, CH3). 13C NMR spectrum (101 MHz, DMSO-d6), δ, ppm (J, Hz): 169.73, 168.50, 142.02, 132.52, 131.99, 129.83, 129.43, 128.62, 128.47, 127.54, 78.16, 34.96, 21.18. Elem. anal. calcd. for C17H17N3O3S2 (%): C 54.38; H 4.56; N 11.19. Found (%): C 54.42; H 4.57; N 11.23.
(R)-4-Methoxy-N′-(2-phenyl-4,5-dihydrothiazole-4-carbonyl)benzenesulfonohydrazide (6d)
White solid, yield 51.5%, m. p. 192–193 °C (EtOAc). \([\alpha]_{\rm{D}}^{20}\) = +14.2 (c 1, MeOH). 1H NMR spectrum (400 MHz, DMSO-d6), δ, ppm (J, Hz): 10.48 (1H, s, NH), 10.13 (1H, s, NH), 7.89 (2H, d, J = 7.4 Hz, Ph-H), 7.84 (2H, d, J = 8.2 Hz, Ph-H), 7.57 (1H, t, J = 7.5 Hz, Ph-H), 7.50 (2H, d, J = 7.4 Hz, Ph-H), 7.05 (2H, t, J = 8.2 Hz, Ph-H), 5.32 (1H, t, J = 8.9 Hz, CH), 3.83 (3H, s, OCH3), 3.75 (1H, dd, J = 10.9 Hz, J = 9.6 Hz, 1/2CH2), 3.59 (1H, dd, J = 10.7 Hz, J = 8.8 Hz, 1/2CH2). 13C NMR spectrum (101 MHz, DMSO-d6), δ, ppm (J, Hz): 169.80, 167.80, 162.06, 132.51, 131.94, 130.28, 128.58, 127.51, 125.07, 114.15, 78.08, 55.54, 35.03. Elem. anal. calcd. for C17H17N3O4S2 (%): C 52.16; H 4.38; N 10.73. Found (%): C 52.19; H 4.38; N 10.77.
(R)-4-Nitro-N′-(2-phenyl-4,5-dihydrothiazole-4-carbonyl)benzenesulfonohydrazide (6e)
White solid, yield 54.2%, m. p. 184–185 °C (EtOAc). \([\alpha]_{\rm{D}}^{20}\) = +14.6 (c 1, MeOH). 1H NMR spectrum (400 MHz, DMSO-d6), δ, ppm (J, Hz): 10.46 (1H, s, NH), 10.14 (1H, s, NH), 7.86 (2H, d, J = 7.4 Hz, Ph-H), 7.82 (2H, d, J = 8.3 Hz, Ph-H), 7.71 (2H, d, J = 7.4 Hz, Ph-H), 7.55 (1H, t, J = 7.5 Hz, Ph-H), 7.50 (2H, dd, J = 7.6 Hz and J = 8.0 Hz, Ph-H), 5.36 (1H, t, J = 8.9 Hz, CH), 3.79 (1H, dd, J = 10.9 Hz, J = 9.5 Hz, 1/2CH2), 3.63 (1H, dd, J = 10.8 Hz, J = 8.6 Hz, 1/2CH2). 13C NMR spectrum (101 MHz, DMSO-d6), δ, ppm (J, Hz): 169.63, 167.92, 165.62, 132.12, 132.10, 131.72, 130.54, 128.76, 127.69, 125.75, 78.41, 35.53. Elem. anal. calcd. for C16H14N4O5S2 (%): C 47.28; H 3.47; N 13.78. Found (%): C 47.31; H 3.49; N 13.82.
(R)-N’-[2-(p-Tolyl)-4,5-dihydrothiazole-4-carbonyl]benzenesulfonohydrazide (6f)
White solid, yield 54.3%, m. p. 187–188 °C (EtOAc). \([\alpha]_{\rm{D}}^{20}\) = +16.5 (c 1, MeOH) 1H NMR spectrum (400 MHz, DMSO-d6), δ, ppm (J, Hz): 10.40 (1H, s, NH), 10.03 (1H, s, NH), 7.80 (2H, d, J = 7.3 Hz, Ph-H), 7.70 (2H, d, J = 8.1 Hz, Ph-H), 7.62 (1H, t, J = 7.5 Hz, Ph-H), 7.49 (2H, t, J = 7.7 Hz, Ph-H), 7.31 (2H, d, J = 8.0 Hz, Ph-H), 5.11 (1H, t, J = 9.0 Hz, CH), 3.56 (1H, dd, J = 10.9 Hz, J = 9.6 Hz, 1/2CH2), 3.24 (1H, dd, J = 11.0 Hz, J = 8.7 Hz, 1/2CH2), 2.37 (3H, s, CH3). 13C NMR spectrum (101 MHz, DMSO-d6), δ, ppm (J, Hz): 169.26, 168.82, 142.42, 139.04, 133.55, 130.02, 129.82, 129.27, 128.68, 128.11, 77.92, 34.77, 21.50. Elem. anal. calcd. for C17H17N3O3S2 (%): C 54.38; H 4.56; N 11.19; Found (%): C 54.39; H 4.63; N 11.23.
(R)-4-Chloro-N′-[2-(p-tolyl)-4,5-dihydrothiazole-4-carbonyl]benzenesulfonohydrazide (6g)
White solid, yield 53.8%, m. p. 179–180 °C (EtOAc). \([\alpha]_{\rm{D}}^{20}\) = +17.8 (c 1, MeOH). 1H NMR spectrum (400 MHz, DMSO-d6) δ, ppm (J, Hz): 10.52 (1H, s, NH), 10.11 (1H, s, NH), 7.82 (2H, d, J = 7.5 Hz, Ph-H), 7.69 (2H, d, J = 8.1 Hz, Ph-H), 7.51 (2H, d, J = 7.5 Hz, Ph-H), 7.24 (2H, d, J = 8.0 Hz, Ph-H), 5.26 (1H, t, J = 9.0 Hz, CH), 3.67 (1H, dd, J = 10.7 Hz, J= 9.4 Hz, 1/2CH2), 3.51 (1H, dd, J = 10.7 Hz, J = 8.4 Hz, 1/2CH2), 2.29 (3H, s, CH3). 13C NMR spectrum (101 MHz, DMSO-d6), δ, ppm (J, Hz): 169.25, 168.14, 141.56, 136.37, 130.72, 129.28, 128.96, 128.93, 128.27, 127.95, 77.59, 34.43, 20.65. Elem. anal. calcd. for C17H16ClN3O3S2 (%): C 49.85; H 3.97; N 10.29; Found (%): C 49.89; H 3.98; N 10.33.
(R)-4-Methyl-N′-[2-(p-tolyl)-4,5-dihydrothiazole-4-carbonyl]benzenesulfonohydrazide (6h)
White solid, yield 63.1%, m. p. 210–211 °C (EtOAc). \([\alpha]_{\rm{D}}^{20}\) = +17.4 (c 1, MeOH). 1H NMR spectrum (400 MHz, DMSO-d6), δ, ppm (J, Hz): 10.29 (1H, s, NH), 10.02 (1H, s, NH), 7.83 (2H, d, J = 7.5 Hz, Ph-H), 7.78 (2H, d, J = 8.0 Hz, Ph-H), 7.01–6.97 (4H, m, Ph-H), 5.26 (1H, t, J = 9.0 Hz, CH), 3.78 (6H, s, CH3), 3.69 (1H, dd, J = 11.0 Hz, J= 9.6 Hz, 1/2CH2), 3.54 (1H, dd, J = 10.9 Hz, J = 8.6 Hz, 1/2CH2). 13C NMR spectrum (101 MHz, DMSO-d6), δ, ppm (J, Hz): 167.74, 165.65, 128.18, 127.52, 127.32, 122.97, 122.78, 122.54, 112.05, 111.70, 75.98, 53.38, 32.94, 32.87. Elem. anal. calcd. for C18H19N3O3S2 (%):C 55.51; H 4.92; N 10.79. Found (%): C 55.54; H 4.96; N 10.83.
(R)-4-Methoxy-N′-[2-(p-tolyl)-4,5-dihydrothiazole-4-carbonyl]benzenesulfonohydrazide (6i)
White solid, yield 54.3%, m. p. 180–181 °C (EtOAc). \([\alpha]_{\rm{D}}^{20}\) = +17.1 (c 1, MeOH). 1H NMR spectrum (400 MHz, DMSO-d6), δ, ppm (J, Hz): 10.36 (1H, s, NH), 10.10 (1H, s, NH), 7.90 (2H, d, J = 7.4 Hz, Ph-H), 7.80 (2H, d, J = 8.3 Hz, Ph-H), 7.34 (2H, d, J = 7.5 Hz, Ph-H), 7.05 (2H, d, J = 8.2 Hz, Ph-H), 5.36 (1H, t, J = 9.1 Hz, CH), 3.84 (3H, s, OCH3), 3.77 (1H, dd, J = 10.8 Hz, J= 9.6 Hz, 1/2CH2), 3.62 (1H, dd, J = 10.8 Hz, J = 8.5 Hz, 1/2CH2), 2.39 (3H, s, CH3). 13C NMR spectrum (101 MHz, DMSO-d6), δ, ppm (J, Hz): 170.38, 169.07, 162.78, 142.64, 130.51, 130.10, 130.08, 129.12, 125.33, 114.49, 78.83, 56.17, 35.61, 21.83. Elem. anal. calcd. for C19H19N3O4S (%): C 53.32; H 4.72; N 10.36. Found (%): C 53.35; H 4.76; N 10.39.
(R)-4-Nitro-N′-[2-(p-tolyl)-4,5-dihydrothiazole-4-carbonyl]benzenesulfonohydrazide (6j)
Yellow solid, yield 57.3%, m. p. 193–194 °C (EtOAc). \([\alpha]_{\rm{D}}^{20}\) = +17.8 (c 1, MeOH). 1H NMR spectrum (400 MHz, DMSO-d6), δ, ppm (J, Hz): 10.60 (1H, s, NH), 10.19 (1H, s, NH), 7.90 (2H, d, J = 7.5 Hz, Ph-H), 7.78 (2H, d, J = 8.1 Hz, Ph-H), 7.59 (2H, d, J = 7.5 Hz, Ph-H), 7.32 (2H, d, J = 8.0 Hz, Ph-H), 5.35 (1H, t, J = 9.0 Hz, CH), 3.76 (1H, dd, J = 10.9 Hz, J = 9.5 Hz, 1/2CH2), 3.60 (1H, dd, J = 10.8 Hz, J = 8.6 Hz, 1/2CH2), 2.37 (3H, s, CH3). 13C NMR spectrum (101 MHz, DMSO-d6), δ, ppm (J, Hz): 171.25, 170.14, 166.09, 143.56, 138.37, 131.28, 130.96, 130.93, 130.27, 129.95, 79.59, 36.43, 22.65. Elem. anal. calcd. for C17H16N4O5S2 (%): C 48.56; H 3.84; N 13.33. Found (%): C 48.58; H 3.89; N 13.38.
(R)-N′-[2-(4-Nitrophenyl)-4,5-dihydrothiazole-4-carbonyl]benzenesulfonohydrazide (6k)
Yellow solid, yield 51.8%, m. p. 211–212 °C (EtOAc). \([\alpha]_{\rm{D}}^{20}\) = +17.3 (c 1, MeOH). 1H NMR spectrum (400 MHz, DMSO-d6), δ, ppm (J, Hz): 10.49 (1H, s, NH), 10.18 (1H, s, NH), 7.92–7.88 (4H, m, Ph-H), 7.61–7.57 (3H, m, Ph-H), 7.50 (2H, t, J = 7.9 Hz, Ph-H), 5.39 (1H, t, J = 8.8 Hz, CH), 3.81 (1H, dd, J = 11.1 Hz, J= 9.4 Hz, 1/2CH2), 3.65 (1H, dd, J = 10.9 Hz, J = 8.6 Hz, 1/2CH2). 13C NMR spectrum (101 MHz, DMSO-d6), δ, ppm (J, Hz): 169.51, 167.62, 165.47, 132.49, 131.97, 131.20, 130.21, 129.01, 128.60, 127.51, 78.21, 35.38. Elem. anal. calcd. for C16H14N4O5S2 (%): C 47.28; H 3.47; N 13.78. Found (%): C 47.32; H 3.52; N 13.83.
(R)-4-Chloro-N′-[2-(4-nitrophenyl)-4,5-dihydrothiazole-4-carbonyl]benzenesulfonohydrazide (6l)
White solid, yield 59.3%, m. p. 198–199 °C (EtOAc). \([\alpha]_{\rm{D}}^{20}\) = +14.9 (c 1, MeOH). 1H NMR spectrum (400 MHz, DMSO-d6), δ, ppm (J, Hz): 10.63 (1H, s, NH), 10.29 (1H, s, NH), 8.37 (2H, d, J = 7.6 Hz, Ph-H), 8.15 (2H, d, J = 8.2 Hz, Ph-H), 7.91 (2H, d, J = 7.5 Hz, Ph-H), 7.60 (2H, d, J = 8.1 Hz, Ph-H), 5.48 (1H, t, J = 8.8 Hz, CH), 3.89 (1H, dd, J = 10.9 Hz, J = 9.6 Hz, 1/2CH2), 3.72 (1H, dd, J = 10.8 Hz, J = 8.7 Hz, 1/2CH2). 13C NMR spectrum (101 MHz, DMSO-d6), δ, ppm (J, Hz): 170.78, 168.99, 166.12, 150.83, 139.20, 138.39, 132.68, 131.25, 130.95, 130.28, 79.84, 37.15. Elem. anal. calcd. for C16H13ClN4O5S2 (%): C 43.59; H 2.97; N 12.71. Found (%): C 43.63; H 2.99; N 12.75.
(R)-4-Methyl-N′-[2-(4-nitrophenyl)-4,5-dihydrothiazole-4-carbonyl]benzenesulfonohydrazide (6m)
White solid, yield 48.9%, m. p. 201–202 °C (EtOAc). \([\alpha]_{\rm{D}}^{20}\) = +16.5 (c 1, MeOH). 1H NMR spectrum (400 MHz, DMSO-d6), δ, ppm (J, Hz): 10.63 (1H, s, NH), 10.22 (1H, s, NH), 7.93 (2H, d, J = 7.7 Hz, Ph-H), 7.80 (2H, d, J = 8.1 Hz, Ph-H), 7.62 (2H, d, J = 7.6 Hz, Ph-H), 7.35 (2H, d, J = 8.0 Hz, Ph-H), 5.37 (1H, t, J = 8.8 Hz, CH), 3.78 (1H, dd, J = 11.0 Hz, J= 9.5 Hz, 1/2CH2), 3.62 (1H, dd, J = 10.9 Hz, J = 8.6 Hz, 1/2CH2), 2.39 (3H, s, CH3). 13C NMR spectrum (101 MHz, DMSO-d6), δ, ppm (J, Hz): 168.75, 167.64, 163.59, 141.06, 130.22, 128.78, 128.46, 128.43, 127.77, 127.45, 77.09, 33.93, 20.15. Elem. anal. calcd. for C17H16N4O5S2 (%): C 48.56; H 3.84; N 13.33. Found (%): C 48.59; H 3.86; N 13.37.
(R)-4-Methoxy-N′-[2-(4-nitrophenyl)-4,5-dihydrothiazole-4-carbonyl]benzenesulfonohydrazide (6n)
White solid, yield 52.5%, m. p. 197–198 °C (EtOAc). \([\alpha]_{\rm{D}}^{20}\) = +14.7 (c 1, MeOH). 1H NMR spectrum (400 MHz, DMSO-d6), δ, ppm (J, Hz): 10.56 (1H, s, NH), 10.13 (1H, s, NH), 7.88 (2H, d, J = 7.3 Hz, Ph-H), 7.81 (2H, d, J = 8.1 Hz, Ph-H), 7.57 (2H, d, J = 7.3 Hz, Ph-H), 7.03 (2H, d, J = 8.2 Hz, Ph-H), 5.30 (1H, t, J = 9.0 Hz, CH), 3.80 (s, 3H, OCH3), 3.72 (1H, dd, J = 10.9 Hz, J = 9.5 Hz, 1/2CH2), 3.56 (1H, dd, J = 10.8 Hz, J = 8.6 Hz, 1/2CH2). 13C NMR spectrum (101 MHz, DMSO-d6), δ, ppm (J, Hz): 169.13, 167.19, 161.45, 136.16, 130.63, 129.64, 128.80, 128.11, 124.43, 113.52, 77.42, 54.92, 34.38. Elem. anal. calcd. for C17H16N4O6S2 (%): C 46.78; H 3.69; N 12.84. Found (%): C 46.85; H 3.73; N 12.87.
(R)-4-Nitro-N′-[2-(4-nitrophenyl)-4,5-dihydrothiazole-4-carbonyl]benzenesulfonohydrazide (6o)
White solid, yield 55.8%, m. p. 189–190 °C (EtOAc). \([\alpha]_{\rm{D}}^{20}\) = +15.1 (c 1, MeOH). 1H NMR spectrum (400 MHz, DMSO-d6), δ, ppm (J, Hz): 10.66 (1H, s, NH), 10.27 (1H, s, NH), 7.98 (2H, d, J = 7.7 Hz, Ph-H), 7.91 (2H, d, J = 8.3 Hz, Ph-H), 7.82 (2H, d, J = 7.6 Hz, Ph-H), 7.68 (2H, d, J = 8.3 Hz, Ph-H), 5.46 (1H, t, J = 8.7 Hz, CH), 3.89 (1H, dd, J = 10.9 Hz, J= 9.6 Hz, 1/2CH2), 3.73 (1H, dd, J = 10.7 Hz, J = 8.8 Hz, 1/2CH2). 13C NMR spectrum (101 MHz, DMSO-d6), δ, ppm (J, Hz): 171.30, 169.66, 166.32, 138.69, 133.80, 133.60, 133.10, 132.22, 131.30, 130.62, 80.07, 37.20. Elem. anal. calcd. for C16H13N5O7S2 (%): C 42.57; H 2.90; N 15.51. Found (%): C 42.59; H 2.95; N 15.54.
(R)-4-Chloro-N′-(2-phenyl-4,5-dihydrothiazole-4-carbonyl)benzenesulfonohydrazide (6p)
White solid, yield 68.3%, mp 184–185 °C (EtOAc). \([\alpha]_{\rm{D}}^{20}\) = +14.6 (c 1, MeOH). 1H NMR spectrum (400 MHz, DMSO-d6), δ, ppm (J, Hz): 10.54 (1H, s, NH), 10.15 (1H, s, NH), 7.87 (2H, d, J = 7.4 Hz, Ph-H), 7.80 (2H, d, J = 8.0 Hz, Ph-H), 7.70 (2H, d, J = 7.5 Hz, Ph-H), 7.56 (2H, t, J = 7.5 Hz, Ph-H), 5.35 (1H, t, J = 8.7 Hz, CH), 3.78 (1H, dd, J = 10.8 Hz, J = 9.5 Hz, 1/2CH2), 3.62 (1H, dd, J = 10.9 Hz, J = 8.8 Hz, 1/2CH2). 13C NMR spectrum, δ, ppm (J, Hz): 167.78, 166.15, 135.18, 130.29, 129.89, 129.60, 128.71, 127.79, 127.11, 123.94, 76.56, 33.69. Elem. anal. calcd. for C16H13Cl2N3O3S2 (%): C 44.66; H 3.05; N 9.77. Found (%): C 44.59; H 3.09; N 9.76.
Biological activity screening
Fungicidal activity
Title compounds 6a–p against six phytopathogenic fungi (Alternaria solani, Physalospora piricola, Cercospora arachidicola, Phytophthora capsici, Fusarium graminearum, and Sclerotinia sclerotiorum) at the concentration of 50 mg/L were determined by the mycelium growth rate test according to the literatures (Liu et al. 2016), and calculated using the formula: Relative inhibition rate (%) = (D1 − D2)/D1 × 100%, D1 and D2 are the average diameter of circle mycelia during the blank assay and test assay, respectively. Chlorothalonil and carbendazim were used as the control. The fungicidal activities of title compounds 6a–p at 50 mg/L were shown in Table 1. The EC50 values of title compounds 6a–o against Phytophthora capsici were displayed in Table 2. The EC50 values of title compound 6p and chlorothalonil against six phytopathogenic fungi were shown in Table 3.
Insecticidal activity against Culex pipiens
The insecticidal activity of title compounds 6a–p with chlorantraniliprole as positive control against Culex pipiens were evaluated in the greenhouse according to the reported method (Liu et al. 2016) in Table 4.
3D-QSAR calculation methods
The CoMSIA studies were carried out using a SYBYL 6.9 software from Tripos Inc (St. Louis, MO, USA). All molecules were built with the SKETCH option in SYBYL under default settings. CoMSIA contour maps were generated with partial least-squares coefficients (Liu et al. 2018). The partial least-squares was carried out to establish a linear relationship. Cross-validation was performed by using the “leave-one-out” method to obtain the optimal number of component and cross-validated coefficient q2. The cross-validated coefficient q2 and non-cross-validated correlation coefficient r2 could estimate the predictive capability and modeling, respectively.
Design of title compounds
Results and discussion
Chemistry
The synthetic routes of the title compounds are shown in Scheme 1. (R)-2-Phenyl-4,5-dihydrothiazole-5-carboxylic acids 3 were prepared by treating benzonitrile derivatives 1 with L-cysteine 2 reference to our previous work (Liu et al. 2015) with some improvement. Intermediates 5 were prepared by treated benzenesulfonylchloride derivatives 4 with hydrazine hydrate in good yields (Backes et al. 2015). Then title compounds 6a–p were prepared in moderate yields by coupling reaction of (R)-2-Phenyl-4,5-dihydrothiazole-5-carboxylic acids 3 and benzenesulfonohydrazides 5 in the presence of N,N-diisopropylethylamine (DIPEA) with 1-hydroxy-1H-benzotriazole (HOBT) and N-(3-dimethylaminopropyl)-N’-ethylcarbodiimide hydrochloride (EDCI) as coupling reagent.
The chemical structures of title compounds 6a–p were determined by 1H NMR, 13C NMR, and elemental analysis (EA). As shown in Fig. 2, the 1H NMR spectra of 6f (Fig. 2a), the two active proton signals of sulfonohydrazide moiety (–SO2NHNHCO–) were observed at 10.40 ppm (s) and 10.03 ppm (s). The signal of CH of the 4,5-dihydrothiazole ring was assigned 5.11 ppm (t). The signals at 3.56 ppm (dd) and 3.24 ppm (dd) were assigned to the CH2 of the 4,5-dihydrothiazole ring due to the adjacent chiral carbon. The 13C NMR spectra of 6f shown in Fig. 2b, the signal of sulfonohydrazide moiety (–SO2NHNHCO–) appeared at 169.26 ppm, and the signals of C=N of the 4,5-dihydrothiazole ring appeared at 168.82 ppm. The signals of CH and CH2 of the 4,5-dihydrothiazole ring appeared at 77.92 ppm and 34.77 ppm, respectively.
1H NMR (a) and 13C NMR (b) of title compound 6f
Antifungal activity and 3D-QSAR
As shown in Table 1, most title compounds against six phytopathogenic fungi exhibited moderate to remarkable (in vitro) activities at the concentration of 50 mg/L, and even better than the control chlorothalonil or carbendazim. Moreover, compounds 6b and 6g exhibited good and broad-spectrum antifungal activities. Among compounds 6a–o, when the substituent R2 was the same, compounds 6a–e (R1 = H) and 6f–j (R1 = CH3) against Alternaria solani, Physalospora piricola, Cercospora arachidicola, Phytophthora capsici, and Fusarium graminearum displayed better inhibitory activities than those of compounds 6k–o (R1 = NO2). However, for Sclerotinia sclerotiorum, the substituent R1 on the benzene ring of title compounds with the same R2 exerted different influences on antifungal activity following the sequence NO2 > H and CH3. Furthermore, 6l (R1 = NO2, R2 = Cl) against Sclerotinia sclerotiorum exhibited 65.3% antifungal activity, more effective than the control chlorothalonil. When the substituent R1 was the same, the antifungal activities of title compounds with the R2 = Cl were better than others. For example, compound 6b (R2 = Cl) against Alternaria solani, Physalospora piricola, Cercospora arachidicola, Phytophthora capsici, Fusarium graminearum, and Sclerotinia sclerotiorum exhibited 55.9, 86.2, 59.7, 75.2, 65.5, and 50% antifungal activities, respectively, better than other compounds 6a and 6c–e. These results indicated that the different types of substituents R1 and R2 had obvious influences on the antifungal activities.
In order to give more information of SAR, based on pEC50 of title compounds against Phytophthora capsici as shown in Table 2, a brief 3D-QASR analysis was carried out using Sybyl 6.9 software. A across validated coefficient of q2 = 0.764, and a correlation coefficient of r2 = 0.989 were obtained as the best CoMSIA model. Due to the lowest EC50 value, compound 6b was used as the template molecule. The order of the relative contribution to the built CoMSIA model was electrostatic (42.4%) > hydrophobic (37.6%) > H-bond acceptor (10.3%) > steric (9.7%) > H-bond donor (0%), revealing that the electrostatic and hydrophobic fields were the chief factors to the antifungal activities. As shown in the electrostatic CoMSIA contour map (Fig. 3a), the red contours around the R2 group revealed that compounds at this position with proper negative charge groups could improve the antifungal activities, agreement with the order of activity in R2 group Cl > H, CH3, OCH3, and NO2. As for the hydrophobic CoMSIA contour map (Fig. 3b), the white contours around the R1 and R2 groups suggested that compounds with proper hydrophilic groups contributed to the antifungal activity, which was consistent in the antifungal activity. These results of the built CoMSIA model will help to the further structural optimization.
The contour map of the electrostatic field (a) and hydrophobic field (b)
Based on the SAR and 3D-QSAR model, for purpose of improving the antifungal activity, we rationally designed and synthesized compound 6p (R1 = Cl, R2 = Cl). The antifungal activity of 6p, as displayed in Tables 1 and 3, was increased to some extent compared with other title compounds, which was consistent with the prediction of the CoMSIA model, revealing that the CoMSIA model displayed good predictability. The EC50 value of 6p was 5.3 mg/L, equal to that of chlorothalonil (5.2 mg/L).
The EC50 values of compound 6p against six phytopathogenic fungi were further tested and the result was shown in Table 3. The EC50 values of compound 6p were comparable to chlorothalonil, which was in agreement with the antifungal acitivities shown in Table 1.
Insecticidal activity against Culex pipiens larvae
The insecticidal activities of title compounds 6a–p against Culex pipiens larvae were tested and shown in Table 4. Most of them displayed moderate to good insecticidal activities at 2 mg/L. On the whole, the insecticidal activities of title compounds 6b, 6g, and 6p with R2 = Cl were better than other compounds at 1 mg/L, in particular, compound 6p exhibited 80% insecticidal activity, comparable to chlorantraniliprole, indicating that the substituent R1 = R2 = Cl played a significant role in the insecticidal activities.
Conclusion
In conclusion, a series of (R)-2-phenyl-4,5-dihydrothiazole-4-carboxamide derivatives containing a sulfonohydrazide moiety were designed and synthesized. Their structures were confirmed by 1H NMR, 13C NMR and EA. All the title compounds were evaluated for fungicidal and insecticidal activities, and most of them against six antiphytopathogenic fungi exhibited moderate to excellent antifungal activities at 50 mg/L. The preliminary SAR was studied. The proper electron withdrawing groups in R2 and proper hydrophilic groups in R1 could improve the antifungal activity. The established CoMSIA model revealed that electrostatic and hydrophobic fields were the two most significant factors for antifungal activity. Therefore, based on the CoMSIA model, structure optimization was performed to find compound 6p (R1 = R2 = Cl) with excellent antifungal activity against Phytophthora capsici, and the EC50 values of compound 6p against six antiphytopathogenic fungi were comparable to those of chlorothalonil. Moreover, the insecticidal activity of compound 6p against Culex pipiens larvae at 1 mg/L was 80%, close to that of chlorantraniliprole. So compound 6p can be used as a novel lead structure for fungicide and insecticide development.
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Acknowledgements
This study was supported by the National Natural Science Foundation of China (nos. 31901908 and 31972287), the Natural Science Foundation of Tianjin (no. 19JCQNJC04600), the Scientific Project of Tianjin Municipal Education Commission (no. 2018KJ008), the National Student’s Platform for Innovation and Entrepreneurship Training Program (no. 201810061003).
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Liu, J., Li, F., Wang, Y. et al. Synthesis, biological activities, and 3D-QSAR studies of (R)-2-phenyl-4,5-dihydrothiazole-4-carboxamide derivatives containing a sulfonohydrazide moiety. Med Chem Res 29, 495–503 (2020). https://doi.org/10.1007/s00044-020-02499-3
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DOI: https://doi.org/10.1007/s00044-020-02499-3