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Cu (II)-catalyzed: synthesis of imidazole derivatives and evaluating their larvicidal, antimicrobial activities with DFT and molecular docking studies


This paper deals with the evaluation of novel imidazole molecules for their antimicrobial and larvicidal activities. A series of imidazole derivatives 1(af) and 2(ae) were prepared by the Mannich base technique using a Cu(II) catalyst. The Cu(phen)Clcatalyst was found to be more effective than other methods. FTIR, elemental analyses, mass spectrometry, 1H NMR, and 13C NMR spectroscopy were performed to elucidate the structures of the synthesised compounds. Antimicrobial and larvicidal activities were investigated for all compounds. The antibacterial activity of compounds (2d) and (2a) were highly active in S.aureus (MIC: 0.25 μg/mL) and K.pneumoniae (MIC: 0.25 μg/mL) compared to ciprofloxacin. Compound (1c) was significantly more effective than clotrimazole in C.albicans (MIC: 0.25 μg/mL). Molecular docking studies of compound 2d showed a higher binding affinity for the 1BDD protein (− 3.4 kcal/mol) than ciprofloxacin (− 4.4 kcal/mol). Compound 1c had a higher binding affinity (− 6.0 kcal/mol) than clotrimazole (− 3.1 kcal/mol) with greater frontier molecular orbital energy and reactivity properties of compound 1c (∆E gap = 0.13 eV). The activity of compound 1a (LD50: 34.9 μg/mL) was more effective in the Culex quinquefasciatus than permethrin (LD50: 35.4 μg/mL) and its molecular docking binding affinity for 3OGN protein (− 6.1 kcal/mol). These newly synthesised compounds can act as lead molecules for the development of larvicides and antibiotic agents.

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Important heterocyclic scaffolds, known as imidazoles, are used in a variety of applications in pharmaceuticals, natural products, endogenous chemicals, and polymers [1]. One of the most prized structures in medicinal chemistry is imidazole, and its derivatives display a variety of biological characteristics, including antidiabetic properties [2, 3]. It is also found in commercial drugs such as clotrimazole (antifungal), dipyrone (antipyretic), rimonabant (antiobesity), miconazole (antifungal), celecoxib (anti-inflammatory), clemizole (antihistaminic agent), (anti-inflammatory). Similarly, azoles are potent compounds with a vast range of therapeutic values, including antimicrobial [4, 5], anti-infective [6], anti-cancer [7], anti-tumor [8], anti-oxidant [9], and anti-viral [10, 11] activities. Azoles are well-known heterocyclic backbones owing to their drug-like properties and binding flexibilities. Naturally, azole derivatives such as pyrazole and imidazole are becoming increasingly important for drug development owing to their extensive biological activities. It is well established that numerous naturally occurring bioactive compounds that are part of this cycle have a wide range of pharmacological activities, including antibiotics [12], antifungals [13], anxiolytics [14], antivirals [15], and aromatase activity [16]. The biological activities of natural products are shown in (Fig. 1).

Fig. 1
figure 1

The Structure of typical of (1-methyl-1H-imidazole) based natural products

The urban mosquito laid eggs in standing water. Typically, in the Praires, the more common mosquito, the Aedes vexans, lays eggs in vegetation around water bodies, usually relying on large rainfall to hatch. Mosquitoes are among the deadliest arthropods in the world. They can act as vectors for various diseases and cause millions of deaths annually [17]. India has long struggled with serious public health issues related to the spread of mosquitoes. Therefore, it is imperative to control mosquitoes to prevent diseases such as West Nile virus infection, including malaria, chikungunya virus infection, yellow fever, lymphatic filariasis, Zika virus infection, and dengue fever, [18]. Various catalysts, such as copper (II) acetate [19], copper (II) acetylacetonate, dihydroxycopper [20], trifluoro methane sulfonate [21], dihydroxycopper, copper hydroxide phosphate, trifluoro methane sulfonate copper (II) [22], copper (II)pyridine, copper (II)chloride, and copper (II)iodide were synthesised through Mannich base derivatives in good yield, and as low yield was obtained in current studies so the dichloro-1,10-phenanthroline copper (II) catalyst was involved in this caltalyst optimisation process. Based on the above observations, this study aimed to synthesise new imidazole Mannich base derivatives using Cu(phen)Cl2 as a catalyst and investigate their antibacterial, antifungal, and larvicidal activities. Therefore, this study aimed to develop the best paradigm for Cu(II)-catalysed synthesis of imidazole derivatives of Mannich bases and to investigate their bioactivity. Since there are no detailed studies on the relationship between larvicidal and antimicrobial activities of imidazoles, the larvicidal and antibacterial effects of the compounds were assessed. The details of the new imidazole made by synthesising analogues and their larvicidal and antimicrobial activities with DFT and molecular docking studies are illustrated in the ongoing work.

Material and methods

All chemicals are used as analytical grade and obtained from Sigma. FTIR (4000–400 cm−1) was used for Thermo Scientific Nicolet iS5. 1H and 13C NMR spectroscopy was used for Bruker DRX-300 MHz and 75 MHz spectrometer. Mass spectra were recorded by Clarus 690–SQ8MS (EI) from PerkinElmer GCMS. An elemental analyser (Model Varioel III) was used to calculate the concentrations of C, H, S, and N.

Synthesis of compounds 1(a–f) and 2(a–e)

A mixture of l-histidine (0.1 mol), benzylidenehydrazine (0.1 mol), aldehyde (0.1 mol), and Cu(phen)Cl2 (10 mol%) was added to 30 ml of ethanol. The reaction mixture was refluxed for 3 h at 35 °C. The compound was identified by TLC using silica plates, and column chromatography was used to separate the final products. An average yield of 78–80% was obtained. All other compounds (1b–f), and (2b–e) were prepared using the same procedure.

Optimization procedure for solvent and catalyst

Mannich base derivatives were prepared from the reactants, imidazole, benzylidene hydrazine, and para-substituted benzaldehyde. The reactions were performed under reflux at room temperature (35 °C) in the presence of Cu(phen)Cl2 catalysts in toluene, CH2Cl2, MeCN, H2O, EtOH, benzene, THF, and DMF. The reaction was carried out at 35 °C for 3 h. A variety of Cu(II)catalyst 10 mol% such as acetylacetonate, dihydroxy copper, copper hydroxide phosphate, trifluoromethanesulfonate, pyridine, dichloro-(1,10-phenanthroline) Cu(II), Cu(II)chloride, and Cu(I) iodide catalysts, have been used to synthesise compounds under reflux in EtOH at room temperature (35 °C) for 3 h.

(2S)-2-Amino-3-(1-(((E)-2-benzylidenehydrazinyl)(phenyl)methyl)-1H-imidazol-4-yl)prop anoicacid (1a)

Yield 72%; Colour Pale yellow; mp 141–147 °C; Rf 0.66; IR(KBr): ν3385 (–NH), 3270 (–NH2), 2983 (–OH), 1730 cm−1; 1H NMR(DMSO-d6, 300 MHz): δ 11.3 (1H, –C=O–OH, s), 8.32 (–CH, 1H, s), 8.35–7.23 (10H, ph ring, m), 7.96, (N=CH–, 1H, s), 7.02 (1H, N–CH–, s),6.97 (1H, –NH–CH, s), 5.14 (2H, CH–NH2, s), 4.16 (1H, C=O–CH, dd, J = 6 Hz, J = 9 Hz), 2.85 (2H, –CH2–, d, J = 6 Hz), 2.0 (1H, s, N–NH);13C NMR(DMSO-d6, 75 MHz): δ 174.9, 143.3, 138.6, 137.8, 136.4, 133.7, 131, 129.2, 128.8, 128.5, 126.9, 126.7, 118.8, 86.0, 55.1, 29.3: EI-MS (m/z): 364.15 (M+, 23.6%); Anal. calcd. for (C20H21NH5O2): C, 66.10; H, 5.82; N, 19.27; %; Found: C, 66.08; H, 5.81; N, 19.25%.

(2S)-2-Amino-3-(1-(((E)-2-benzylidenehydrazinyl)(4-hydroxyphenyl)methyl)-1H-imidazol-4-yl)propanoic acid (1b)

Yield 79%; Colour Light brown; mp 140–142 °C; Rf 0.79; IR(KBr): ν3416 (–NH2), 3382 (–NH), 2857 (–OH), 1728 cm−1; 1H NMR(DMSO-d6, 300 MHz): δ 11.3 (–OH, 1H, s); 8.39 (1H, –CH, s), 8.35–7.51 (5H, Ar ring, m), 7.96 (N = CH–, 1H, s), 7.12–7.04 (4H, ph ring, d, J = 6 Hz), 7.03 (1H, N–CH–, s), 6.99 (1H, NH–CH, s), 5.35 (1H, Ph-OH, s), 5.11 (2H, CH-NH2, s), 4.16 (1H, CH2-CH, dd, J = 6 Hz, J = 9 Hz), 2.83:2.80 (2H, -CH2-, d, J = 6 Hz), 2.0 (N–NH, 1H, s); 13C NMR(DMSO-d6, 75 MHz): δ 174.4, 156.5, 143.3, 137.8, 136.4, 133.7, 131.2, 131.0, 129.2, 128.8, 128.3, 118.8, 115.7, 86.0, 55.1, 29.3: EI-MS (m/z): 380.17 (M+, 22%); Anal. calcd. for (C20H21N5O2): C, 63.31; H, 5.58; N, 18.46%; Found: C, 63.29; H, 5.56; N, 18.43%.

(2S)-2-Amino-3-(1-(((E)-2-benzylidenehydrazinyl)(4-chlorophenyl)methyl)-1H-imidazol-4-yl)propanoic acid (1c)

Yield 81%; Colour Pale yellow; mp 135–139 °C; Rf 0.34; IR(KBr): ν3398 (–NH), 3301 (–OH), 3274 (–NH2), 1725 cm−1; 1H NMR(DMSO-d6, 300 MHz): δ 11.3 (1H, –C=O–OH, s); 8.31 (–CH, 1H, s), 8.35–7.54 (5H, Ar ring, m), 7.96, (1H, N=CH–, s), 7.06–7.04 (ph ring, 4H, d, J = 6 Hz), 7.03 (N–CH–, 1H, s), 6.99 (1H, NH–CH, s), 5.14 (2H, CH–NH2, s), 4.16 (1H, CH2–CH, dd, J = 6 Hz, J = 9 Hz), 2.83 (2H, d, J = 6 Hz, CH2–), 2.0 (N–NH, 1H, s); 13C NMR(DMSO-d6, 75 MHz): δ 174.7, 143.3, 137.8, 136.7, 136.4, 133.7, 132.3, 131.0, 129.2, 128.8, 128.6, 128.3, 118.8, 55.1, 29.3; EI-MS (m/z): 399.13 (M+, 32.8%); Anal. calcd. for (C20H20ClN5O2): C, 60.34; H, 5.09; N, 17.61%; Found: C, 60.36; H, 5.04; N, 17.58; %.

(2S)-2-Amino-3-(1-(((E)-2-benzylidenehydrazinyl)(4-nitrophenyl)methyl)-1H-imidazol-4-yl)propanoic acid (1d)

Yield 83%; Colour White Solid; mp 167–171 °C; Rf 0.57; IR(KBr): ν3380 (–NH), 3327 (–OH), 3296 (–NH2), 1738 cm−1; 1H NMR(DMSO-d6, 300 MHz): δ 11.3 (–C=O–OH, 1H, s); 8.31 (1H, –CH, s); 8.35–7.52 (5H, Ar ring,m); 7.96, (N=CH–, 1H, s), 7.09–7.04 (ph ring, 4H, d, J = 6 Hz), 7.02 (N–CH–, 1H, s), 6.94 (1H, NH–CH, s), 5.11 (2H, CH–NH2, s), 4.16 (1H, CH2–CH, dd, J = 6 Hz, J = 9 Hz), 2.83 (2H, –CH2–, d, J = 6 Hz), 2.2 (s, 1H, N–NH); 13C NMR(DMSO-d6, 75 MHz): δ 174.7, 145.9, 144.7, 143.3, 137.8, 136.4, 133.7, 131.0, 129.2, 128.8, 127.8, 123.7, 118.8, 86.0, 55.1, 29.3; EI-MS (m/z): 409.16 (M+, 22%); Anal. calcd. for (C20H20N6O4): C, 58.82; H, 4.94; N, 20.58%; Found: C, 58.80; H, 4.91; N, 20.56%.

(2S)-2-Amino-3-(1-(((E)-2-benzylidenehydrazinyl)(4-methoxyphenyl)methyl)-1H-imidazol-4-yl)propanoic acid (1e)

Yield 78%; Colour Light brown; mp 176–182 °C; Rf 0.61; IR(KBr): ν3378 (–NH), 3302 (–NH2), 2844 (–OH), 1737 cm−1; 1H NMR(DMSO-d6, 300 MHz): δ 11.3 (–C=O–OH,1H, s), 8.36 (1H, –CH, s), 8.35–7.52 (5H, Ar ring, m), 7.96, (N=CH–, 1H, s), 7.06–7.04 (4H, ph ring, d, J = 6 Hz), 7.02 (N–CH–, 1H, s), 6.99 (1H, NH–CH, s), 5.11 (2H, CH–NH2, s), 4.16 (1H, CH2–CH, dd, J = 6 Hz, J = 9 Hz), 3.83 (3H, O–CH3, t), 2.80:2.83 (2H, –CH2–, d, J = 6 Hz), 2.1 (N–NH, 1H, s); 13C NMR(DMSO-d6, 75 MHz): δ 174.7, 158.8, 143.0, 137.8, 136.4, 133.7, 131.9, 131.0, 130.9, 129.2, 128.9, 127.9, 118.8, 114.1, 6.0, 55.8, 55.1, 29.3; EI-MS (m/z): 394.18 (M+, 24.7%); Anal. calcd. for (C21H23N5O3): C, 64.11; H, 5.89; N, 17.80%; Found: C, 64.09; H, 5.86; N, 17.78%.

(2S)-2-Amino-3-(1-(((E)-2-benzylidenehydrazinyl)(4-(dimethylamino)phenyl)methyl)-1H-imidazol-4-yl)propanoic acid (1f)

Yield 80%; Colour Pale yellow; mp 146–152 °C; Rf 0.62; IR(KBr): ν3380 (–NH), 3300 (–NH2), 3298 (–OH), 1729 cm−1; 1H NMR(DMSO-d6, 300 MHz): δ 11.3 (–C=O–OH, 1H, s), 8.39(–CH, 1H, s), 8.35–7.52 (5H, Ar ring, m), 7.96, (1H, N=CH–, s), 7.05–7.02 (4H, Ph ring, d, J = 3 Hz), 7.02 (1H, –N–CH–, d, J = 3 Hz), 6.94 (NH–CH, 1H, s), 5.11 (CH–NH2, 2H, s), 4.16 (CH2–CH, 1H, dd, J = 6 Hz, J = 9 Hz),2.83 (d, 2H, J = 6 Hz, –CH2–), 3.06 (6H, N–(CH3)2, s), 2.1 (N–NH, 1H, s); 13C NMR(DMSO-d6, 75 MHz): δ 174.7, 149.0, 143.4, 137.8, 136.4, 133.7, 131.0, 129.2, 128.8, 128.1, 127.8, 118.8, 112.7, 86.0, 55.1, 41.3, 29.3; EI-MS (m/z): 407.22 (M+, 24.2%); Anal. calcd. for (C22H26N6O): C, 65.04; H, 6.47; N, 20.65%; Found: C, 65.00; H, 6.43; N, 20.66%.

(2S)-2-Amino-3-(1-((E)-1-((E)-2-benzylidenehydrazinyl)-3,7-dimethylocta-2,6-dien-1-yl)-1H-imidazol-4-yl)propanoic acid (2a)

Yield 73%; Colour Light brown; mp 158–160 °C; Rf 0.42; IR(KBr): ν3375 (–NH), 3296 (–NH2), 3081 (–OH), 1744 cm−1; 1H NMR(DMSO-d6, 300 MHz): δ 11.5 (–OH, 1H, s), 8.36 (–CH, 1H, s), 8.35–7.52 (5H, Ar ring, m), 7.83 (–NH, 1H, s), 6.88 (–CH, 1H, s), 6.64 (–N–C, 1H, s), 5.31 (1H, s), 5.18 (1H, –CH, s), 5.11 (2H, –OH, s), 4.16 (1H, CH2–CH, dd, J = 6 Hz, J = 9 Hz), 2.83 (–CH2–, d, J = 6 Hz, 2H), 2.18 (2H, –CH2, s), 2.2 (1H, –NH, s), 1.98 (2H, –CH2, s), 1.85 (3H, s, –C–CH3), 1.81 (–CH3, 3H, s), 1.68 (–C–CH3, 3H, s); 13C NMR(DMSO-d6, 75 MHz): δ 174.4, 143.3, 137.8, 136.4, 136.2, 135.5, 133.7, 132.0, 131.4, 131.0, 129.2, 128.8, 123.5, 118.8, 118.1, 79.3, 55.1, 39.4, 29.3, 27.6, 24.6, 18.6, 16.1; EI-MS (m/z): 424.27 (M+, 26.4%); Anal. calcd. for (C24H31N5O2): C, 67.46; H, 7.63; N, 17.10%; Found: C, 67.45; H, 7.60; N, 17.11%.

(2S)-2-Amino-3-(1-(1-((E)-2-benzylidenehydrazinyl)-3-methylbut-2-en-1-yl)-1H-imidazol-4-yl)propanoic acid (2b)

Yield 76%; Colour Light brown; mp 163–165 °C; Rf 0.47; IR(KBr): ν3350 (–NH), 3297 (–NH2), 2837 (–OH), 1746 cm−1; 1H NMR(DMSO-d6, 300 MHz): δ 11.5 (–OH, 1H, s), 8.36 ( s, 1H, –CH), 8.35–7.52 (5H, Ar ring, m), 7.84 (–NH, 1H, s), 6.88 (1H, –CH, s), 6.63 (s, 1H, –N–C), 5.33 (1H, –H, s), 5.11 (2H, –NH2, s), 4.16 (1H, CH2–CH, dd, J = 6 Hz, J = 9 Hz), 2.80;2.83 (2H, d, J = 6 Hz, –CH2–), 2.0 (1H, –NH, s), 1.82 (–CH3,3H, s), 1.68 (s, –CH3, 3H); 13C NMR(DMSO-d6, 75 MHz): δ 174.7, 143.3, 137.8, 136.4, 133.7, 131.8, 131.0, 129.2, 128.8, 119.5, 118.8, 79.0, 55.1, 24.3, 18.3; EI-MS (m/z): 342.19 (M+, 19.8%); Anal. calcd. for (C18H23N5O2): C, 63.35; H, 6.76; N, 20.53%; Found: C, 63.38; H, 6.76; N, 20.49%.

(2S)-2-Amino-3-(1-(((E)-2-benzylidenehydrazinyl)(furan-2-yl)methyl)-1H-imidazol-4-yl)propanoic acid (2c)

Yield 81%; Colour Light yellow; mp 178–181 °C; Rf 0.53; IR(KBr): ν3395 (–NH), 3300 (–NH2), 2936 (–OH), 1742 cm−1; 1H NMR(DMSO-d6, 300 MHz): δ 11.5 (–OH, 1H, s), 8.37 (–CH, 1H, s), 8.35–7.52 (5H, Ar ring, m), 7.83 (1H, –NH, s), 7.62–7.64 (3H, Furan, dd, J = 6 Hz, J = 9 Hz),6.87(1H, –CH, s), 6.62 (1H, –N–C, s), 5.11 (2H, –OH, s), 4.16 (1H, CH2–CH, dd, J = 6 Hz, J = 9 Hz),2.83 (2H, –CH2–, d, J = 6 Hz), 2.1 (1H, s, –NH); 13C NMR(DMSO-d6, 75 MHz): δ 174.9, 152.5, 143.3, 142.1, 137.8, 136.4, 133.7, 131.0, 129.2, 128.8, 118.8, 110.6, 106.7, 87.2, 55.1, 29.3; EI-MS (m/z): 354.15 (M+, 21.4%); Anal. calcd. for (C18H19N5O3): C, 61.19; H, 5.40; N, 19.85%; Found: C, 61.16; H, 5.40; N, 19.81%.

(2S)-2-Amino-3-(1-(((E)-2-benzylidenehydrazinyl)(pyridin-4-yl)methyl)-1H-imidazol-4-yl)propanoic acid (2d)

Yield 83%; Colour White Solid; mp 145–149 °C; Rf 0.61; IR(KBr): ν3385 (–NH), 3324 (–OH), 3285 (–NH2), 1744 cm−1; 1H NMR(DMSO-d6, 300 MHz): δ 11.3 (1H, –OH, s), 8.54–8.50 (4H, pyridine, d, J = 6 Hz), 8.34 (s, 1H, –CH), 7.88–7.83 (Ar ring, m, 5H), 7.84 (–NH, 1H, s), 6.88 (s, –CH, 1H), 6.63 (1H, –N–C, s), 5.11 (2H, –OH, s), 4.16 (2H, CH2–CH, dd, J = 6 Hz, J = 9 Hz), 2.83 (d, J = 6 Hz, –CH2–, 2H), 2.3 (1H, s, –NH); 13C NMR(DMSO-d6, 75 MHz): δ 174.7, 149.8, 146.5, 143.3, 137.8, 136.4, 133.7, 131.0, 129.2, 128.8, 124.2, 118.8, 86.0, 55.1, 29.3; EI-MS (m/z): 365.17 (M+, 20.9%); Anal. calcd. for (C19H20N6O2): C, 62.62; H, 5.53; N, 23.06%; Found: C, 62.59; H, 5.50; N, 23.04%.

(2S)-2-Amino-3-(1-(((E)-2-benzylidenehydrazinyl)-3-phenylallyl)-1H-imidazol-4- yl)propanoic acid (2e)

Yield 80%; Colour White Solid; mp153–159 °C; Rf 0.29; IR(KBr): ν3340 (–NH), 3295 (–NH2), 3091 (–OH), 1740 cm−1; 1H NMR (DMSO-d6, 300 MHz): δ 11.2 (–OH, 1H, s), 8.36 (s, 1H, ph–CH–), 8.35–7.52 (5H, Ar ring, m), 7.83 (1H, –NH,s), 7.38–7.24 (5H, Ar ring, m), 6.88 (1H, –CH, s), 6.62 (1H, –N–C, s), 6.56–6.19 (2H, C–H, s), 5.11 (2H, –OH, s), 4.19 (1H, d, J = 6 Hz, d, J = 9 Hz,–CH2–CH), 2.84 (2H, d, J = 6 Hz,–CH2–), 2.3 (–NH, 1H, s); 13C NMR (DMSO-d6, 75 MHz): δ 174.9, 137.6, 136.3, 133.7, 129.5, 129.2, 128.8, 128.6, 128.5, 127.9, 123.3, 118.8, 85.4, 55.1, 29.3; EI-MS (m/z): 390.19 (M+, 24.1%); Anal. calcd. for (C22H23N5O2): C, 67.83; H, 5.98; N, 17.96%; Found: C, 67.83; H, 5.92; N, 17.96%.

Biological screening


The Microbial Type Culture Collection Centre, Institute of Microbial Technology, Chandigarh, India, provides the varies microorganisms. All test microorganisms were kept alive on nutritional agar slants (HiMedia) maintained at 4 °C. The assay was performed using disk diffusion and broth dilution methods. Staphylococcus aureus (MTCC 96), Escherichia coli (MTCC 739), Pseudomononas aeruginosa (MTCC 2453), Klebsiella pneumoniae (MTCC 109), and were used for the antibacterial test. Antifungal tests were performed in Candida albicans (MTCC 183), Microsporum audouinii (MTCC 739), Cryptococcus neoformans (a clinical isolate), and Aspergillus niger (MTCC 872). Fresh cultures of each microbe a loop containing the were formed by transferring stock culture inoculum into test tubes containing autoclaved nutrient broth.

In vitro antibacterial screening

Compounds 1(af) and 2(ae) were tested in S. aureus, E. coli, P.aeruginosa, and K. pneumoniae. Bacterial inocula were prepared from fresh overnight cultures, suspended in 0.85% saline, and adjusted to a McFarland turbidity of 0.5. Mueller–Hinton agar (HiMedia, India) was uniformly streaked over the suspension. A sterile cork borer was used to create a well measuring five millimeters in diameter, which was filled with 100 µL of the test compound (100 μg/mL). The positive control was ciprofloxacin and the negative control was DMSO. The plates were incubated at 37 °C for 24 h. Three sets of tests were conducted to validate the findings statistically.

In vitro antifungal screening

Antifungal activity in C. albicans, C. neoformans, and M. audouiniiwas evaluated for compounds 1(a–f), and 2(a–e) using the method described above. Positive and negative controls were used to validate the inferences.

Determining the minimal inhibitory concentration (MIC)

Compounds 1 (af) and 2 (ae) were dissolved in 64 μg/mL DMSO. The solutions at 64, 32, 16, 8, 4, 2, 1, 0.5, and 0.25 μg/mL were made using a twofold dilution. In each well, 106 colonies of microbes per millilitre (unit/mL) of suspension were cultured for 24 h at 37 °C. The minimal inhibitory concentrations of compounds with no noticeable growth were identified.

Larvicidal activity

The susceptibility of C. quinquefasciatus to compounds 1(af) and 2(ae) was determined using a standard bioassay protocol as described in our previous work. The 2 and 3 stage larvae (ten/vial) were placed in a test vial. Mortality was checked using various concentrations (10, 25, 50, and 100 μg/mL) of the synthesised compounds 1(a–f), 2(a–e), and positive (DMSO) and negative (without vehicle) controls after a 24 h exposure period, and the number of surviving larvae was recorded. To verify the outcomes, each experiment was performed three times.

Molecular docking analysis

To identify the mode of interaction, molecular docking experiments were completed, and the binding of the most potent molecules in the imidazole series (2d, 1c, and 1a) and proteins 1BDD, 1AI9, and 3OGN were assessed using AutoDock Vina 1.1.2. The highly active compounds in the molecular docking models were compared with standard drugs such as ciprofloxacin, clotrimazole, and permethrin.

Results and discussion


The three-component reactions of l-histidine, benzylidenehydrazine, and aldehydes were carried out using a conversion method to create Mannich-based imidazole derivatives. The reaction sequence is showed in Scheme 1. Various solvents such as MeCN, THF, toluene, CH2Cl2, EtOH, benzene, H2O, and DMF, and various Cu(II) catalysts were used to optimise the reaction for 1a. The Cu(phen)Cl2 catalyst gave an excellent yield compared to other Cu(II) catalysts. The Cu(phen)Cl2 catalyst was produced in higher yields for compound 1a in ethanol solvent (Table 1, entry 7). Under optimum conditions, imidazole, benzylidene hydrazine, and Cu(II) catalysts using different aldehydes together with para-substituted benzaldehyde produced imidazole derivatives 1(a–f) and 2(a–e) in good yields. Using 10 mol% Cu(phen)Cl2 in ethanol, the target product 1a was prepared with dichloro-(1,10-phenanthroline)-copper (II) in 92% yield within 3 h. The high catalytic activity of 1a is summarised in Table 2.

Scheme 1
scheme 1

The synthetic route of compounds (1a-f) and (2a-e)

Table 1 The compound 1a from different solvent with Cu(Phen)Cl2 catalyst
Table 2 The compound 1a synthesized from ethanol solvent with different Cu(II) catalyst

The infrared spectra of all compounds were observed at 3398–3375, 3298–2837, 3416–3270, and 1750–1730 cm−1, corresponding to the –C=O, –NH, –OH, and –NH2 groups, respectively. Compound 1a's 1H NMR spectrum reveals that its chemical shift of 1a was 118.1 ppm. This corresponds to the proton OH bound to the carbonyl group, a singlet in this region, while δ 8.36 corresponds to the proton Ph- CH (d, J = 3 Hz) with a singlet. The chemical shift of δ 7.96 corresponds to the –N=CH– proton in a singlet. The chemical shift δ 7.83–7.26 corresponds to the 5H protons in the phenyl ring representing mutilate in this reignite. A chemical shift of δ 7.02 corresponds to singlets in the region, which is represented by the –N–CH– group. Another chemical shift, δ 6.11, corresponds to the proton –NH–CH– means, a singlet in this region. The chemical shift δ 5.13 corresponds to the 2H proton in the –CH–NH2 group, indicating this region's singlet. The chemical shift δ 4.16 (dd, J = 6 Hz, J = 9 Hz) corresponded to the 1H proton in the –CO–CH–group, which correlated with the singlet in this region. The chemical shift δ 3.11 (d, J = 6 Hz) corresponded to the 1H proton in the –CH–group, which coincided with the singlet in this region. The chemical shift δ 2.86 corresponds to the 1H proton in the –CH– group and δ 2.0 was observed the 1H proton in the –N–NH group, which matched the singlet in this region. The common chemical shift values of δ 8.3–7.96, 11.0–5.11 and 5.13–4.18 correspond to the –N = CH, –OH, and –NH2 protons, respectively, present in all the synthesised compounds 1(b–f) and 2(a–e).

The 13C NMR chemical shift value of compound 1a showed that the signals at δ 174.7 corresponded to the –C = O of the carbon present in the carboxyl group. The chemical shift value of δ 143.3 corresponds to the –CH group presence in compound 1a, the δ 138.6–126.9 corresponds to the present in the aromatic ring, the δ 137.8–118.8 corresponding to the present in the imidazole, the value of δ 133.7–128.8 representing the in the aromatic ring, the value of δ 86.0 representing the –CH– presence. The values of δ 55.1 and 29.3 correspond to –CH– and –CH2– carbons, respectively. The common chemical shift values of δ 174.7, 143.3–137.8, 137.8–118.6, and 55.1 ppm corresponded to the –CO, –C = C, –C = N and –C–NH2 groups present in all synthesised compounds 1(b–f) and 2(a–e), respectively. Mass spectrometry was used to determine the molecular weight of 1a, which showed that the molecular ion peak corresponded to EI-MS (m/z):364.15 (M + , 10%). The structures of the components were verified by mass spectroscopy and elemental analysis. Compounds 1(b–f) and 2(a–e) were characterised following the method described above for compound 1a. FTIR, NMR, and mass spectraum (Additional file 1: Fig. S1–S42) are presented, and the 1H and 13C NMR values are tabulated and presented in Supporting Information (Additional file 1: Table S1–11 and Fig. S43–53).

Biological activities

Antibacterial activity

Compounds 1(a–f) and 2(a–e) were evaluated for their antibacterial activities in both gram-positive and gram-negative bacteria [23]. Compound 2d was more active in S. aureus (MIC: 0.25 μg/mL) than ciprofloxacin (MIC: 0.5 μg/mL). Compound 2a showed higher activity in K. pneumonia (MIC: 0.25 μg/mL) than ciprofloxacin (MIC:32 μg/mL). In contrast, compounds 1a, 1b, 1c, 1d, 1e, and 2b showed lower activity in all bacterial strains than that of the ciprofloxacin standard (MIC: 32 μg/mL). Compound 2c showed similar activity in S. aureus (MIC: 0.5 μg/mL) compared to ciprofloxacin (MIC:0.5 μg/mL). In addition, it was highly active in K. pneumoniae (MIC: 0.5 μg/mL). Compound 1e exhibited equipment activity in K. pneumoniae (MIC: 32 μg/mL) compared to standard. These values are presented in Tables 3 and 5, respectively.

Table 3 Compounds 1 (af), 2 (ae), and zone of inhibition/mm's antibacterial activity

Antifungal activity

The antifungal activities of compounds 1(a–f) and 2(a–e) were evaluated using the disc diffusion method [24] in C. neoformans, C. albicans, and M. audouinii fungal strains. Compound 1c was more effective in C. albicans (MIC: 0.25 μg/mL) than cotrimazole (MIC:0.5 g/mL). Compound 1b was highly activity in C. albicans (MIC:0.25 μg/mL) than clotrimazole. Compounds 1b, 2a, and 2b were more active in A. niger (MIC: 16 μg/mL) than clotrimazole. Compounds 1a and 2d showed equipment activity (MIC: 16 μg/mL) in Cryptococcus neoformans compared to clotrimazole. These values are accessible in Tables 4 and 5, respectively.

Table 4 Compounds 1 (af), and 2 (ae), zone of inhibition/mm's antifungal activity
Table 5 Compounds 1(af), 2(ae), minimal inhibitory concentrations

Larvicidal activity

The larvae of the second instar of C. quinquefasciatus were used for larvicidal screening [25] of all synthesised compounds 1(a–f) and 2(a–e). Compound 1a showed higher activity (LD50: 34.9 μg/mL) than other compounds and permethrin (LD50: 35.4 μg/mL). Compounds 1c, 2a, and 2e showed nearly equipotent activity compared to that of permethrin. Compound 2c had an LD50 value greater than or equal to 100 μg/mL, indicating its low activity in C. quinquefasciatus. The values are listed in Table 6.

Table 6 Larvicidal profiles of compounds 1(a–f), 2(a–e) on Culex sp. second-instar larvae

Structure–activity relationship

The synthesised compounds 1(a–f) and 2(a–e) were examined for their relationship with structure and activity. Compounds 1a, 1b, 1c, 2a, 2c, 2d, and 2e were particularly active. Figure 2 shows the structure–activity relationship.

Fig. 2
figure 2

Previous and current of structure–activity relationship

Compound 1(a) have para -Cl in phenyl ring, which is highly active in S. aureus (MIC:0.25 μg/mL) than ciprofloxacin (MIC:0.5 μg/mL) [26]. Compound 1b, an imidazole moiety, showed the most effective antibacterial action because of its small size and improved ability to enter the bacterial cells. Compound 1b's antibacterial activity was reduced by chlorine at the para position of the phenyl ring on the imidazole derivatives (MIC: 1–4 g/mL) [27]. This area plays a biological role in imidazole and the para-substituted phenyl ring. In antifungal screening, compound 1c, which has an –N(CH3)2 group in the phenyl ring, showed higher activity in C. neoformans and S. aureus [28]. In comparison with ciprofloxacin (pyridine-3-carboxylic acid), compound 2d (pyridine ring moiety with imidazole moiety and 2-amino acetic acid) (MIC: 0.25 g/mL) showed significantly higher activity in S. aureus. Similar to ciprofloxacin, compound 2d showed high activity in K. pneumoniae (MIC: 0.25 μg/mL). Compound 2c, which contains a furan and imidazole moiety with 2-amino acetic acid, exhibits higher action in S. aureus and K. pneumonia (MIC: 0.5 μg/mL) in comparison to standard ciprofloxacin (MIC: 0.5 μg/mL). In addition, compound 1e (anisole connected with an imidazole moiety and 2-amino acetic acid) exhibited equipotential activity (MIC: 32 μg/mL) in K. pneumoniae compared to ciprofloxacin. Antibacterial and antifungal activities have been demonstrated in recent studies. The biphenyl carboxamide connected to an imidazole moiety was able to create essential antifungal agents and fluconazole (MIC: 2–8 μg/mL), highly active C. tropicalis, and C. albicans (MIC:0.5 μg/mL). However, halogen groups in the ortho or para positions of the aromatic ring increase the effects because they act as electron-donating groups [29]. Previous studies have aimed to clarify the mechanism through which 5-aminoimidazole-4-carbohydrazonamide derivatives act as antifungal agents in C. albicans (MIC: 32–64 μg/mL) and C. krusei (MIC: 4–8 μg/mL) compound 2(b) with fluconazole. The relationship with this antifungal medication results from the suppression of the C. albicans virulence mechanism, which is a dimorphic transition [30]. Compound 2(c), which has a para-NO2 group, demonstrated effective antifungal activity in C. albicans(MIC: 0.25 μg/mL) than other synthesised compounds and clotrimazole (MIC:1 μg/mL) [26]. Compound 1a, which contains an imidazole moiety with 2-amino acetic acid, and 1c, which contains para-chlorophenyl and an imidazole moiety with 2-amino acetic acid, 1d, and 2c, which contain a furan and an imidazole moiety with 2-amino acetic acid, were all equally effective in A. niger and clotrimazole. Compounds 1b, 2a, and 2b were more active in A. niger than the clotrimazole. Compound 1c (4-chloro phenyl and imidazole moiety with 2-amino acetic acid) was highly active in C. albicans (MIC: 0.25 μg/mL) than standard clotrimazole (MIC: 0.5 μg/mL). Clotrimazole (MIC: 0.5 μg/mL) compared to compound 1b (4-hydroxyl phenyl and imidazole moiety with 2-amino acetic acid) showed more equipment activity. Compounds 1a (imidazole moiety with 2-amino acetic acid) and 2d showed equipotent activity (MIC: 16 μg/mL), whereas compound 1d (pyridine ring and imidazole moiety with 2-amino acetic acid) had equipotent activity (MIC: 16 μg/mL) compared than clotrimazole (MIC: 16 μg/mL). Previous and present studies of larvicidal activity: As an effective larvicide (LD50: 9.5 μg/mL) due to compound 3(a) containing a para-CH3-phenyl, thiosemicarbazone and imidazole ring [26]. larvicidal screening, compound 3(b), which has a 2,6-dimethylocta-2,6-diene group, is highly toxic (LD50: 0.75 μg/mL) compared to other compounds [28]. Compared to permethrin, compound 1a (imidazole moiety with 2-amino acetic acid) showed higher larvicidal activity (LD50: 34.9 μg/mL). When compared to permethrin, the activities of compounds 1c (4-chloro phenyl and imidazole moiety with 2-amino acetic acid), 2a (citral connected with imidazole moiety with 2-amino acetic acid), and 2e (cinnamaldehyde connected with imidazole moiety with 2-amino acetic acid) were virtually equal to LD50values more than or equal to 100 μg/mL, while compound 2c (furan and imidazole moiety with 2-amino acetic acid) exhibited low activity in C. quinquefasciatus. The above pieces of evidence indicate the relationship between the antibacterial, antifungal, and larvicidal activities of previous and current studies, as shown in (Fig. 2).

Molecular docking studies with auto dock vina

The processes of adsorption and interactions among the most potent molecules in the imidazole series (i.e. 2d, 1c, and 1a) and proteins 1BDD, 1A19, and 3OGN were investigated using molecular docking studies with AutoDock Vina 1.1.2. The outcomes were evaluated using reference molecular docking models. Ciprofloxacin, clotrimazole, and permethrin were used to compare molecular docking studies. Staphylococcus aureus protein a (PDB ID:1BDD), Candida albicans (PDB ID :1AI9), and odourant-binding protein (PDB ID:3OGN) were obtained from the Protein Data Bank.

ChemDraw Ultra software used for draw the 3D structures of 2d, 1c, and 1a (Figs. 3, 4, 5). The standard settings to support the Vina docking program were used for all other parameters that are not listed in this document. The substance with the lowest binding-affinity rating also had the highest score. All data were visually analysed using Discovery Studio 2019 software. Using the 1BDD, 1AI9, and 3OGN proteins in the Auto Dock Vina program, the docking abilities of the most effective synthetic compounds (2d, 1c, and 1a) were investigated. In this case, the S.aureus protein binding score 2d demonstrated a greater binding affinity for 1BDD (− 3.4 kcal/mol) and ciprofloxacin (− 4.4 kcal/mol) (Table 7). As a result, interacting residues were found in Asp 3, Lys 5, Lys 8, and Gln 10, with respect bond lengths of 1.73, 2.12, 2.00, and 2.23 compared with the standard ciprofloxacin found in Phe 6 and Lys 36, corresponding to bond lengths of 5.76, 1.93, respectively.

Fig. 3
figure 3

The molecular docking studies of compound 2d and Ciprofloxacin binding with 1BDD protein

Fig. 4
figure 4

The molecular docking studies of compound 1c and Clotrimazole binding with 1AI9 protein

Fig. 5
figure 5

The molecular docking studies of compound 1a binding with 3OGN Protein

Table 7 Molecular Docking Interactions of 2d, 1c, and 1a

Antifungal activity of compound 1c was establishes two hydrogen-bonding connections with receptor 1AI9. The docking score (− 6.0 kcal/mol) was compared with that of clotrimazole (− 3.1 kcal/mol) with interacting residues involving Ile 19, Phe 36, Ile 112, and Ala 115, with bond lengths of 2.54, 4.81, 2.29, and 1.94, compared with clotrimazole Thr 106 with band length 1.76, receptivity. Larvicidal activity 1a (− 6.1 kcal/mol) interactions with the 3OGN protein and its receptors involved two hydrogen bonds. In this instance, the interactions involving residues His 111, Trp 114, and Phe 123, which had bond lengths of 5.44, 5.29, and 4.01, respectively, in the molecular docking interaction of 3OGN protein with permethrin, as detailed in our previous study [22]. Overall, the findings revealed that compounds 2d, 1c, and 1a had more antibacterial, antifungal, and larvicidal activities than the reference standards.

HOMO–LUMO analysis

The most crucial components of the HOMO–LUMO analysis are the electrical and chemical reactions of 2c, 2a, and 1c. "Donate an electron" and "receive an electron”, respectively, are the definitions of the acronyms HOMO and LUMO. As mentioned earlier, the forces behind the compounds are depicted in (Fig. 6) as the HOMO and LUMO energies, estimated using the DFT approach combined with the B3LYP/631G Basic Set (d, p). Generally, a compound is soft when the HOMO and LUMO energy differences are minimal, and complex when they are high. The parameters regarded the terms "lowest unoccupied molecular orbital" and "highest occupied molecular orbital" as acute in limiting the chemical stability and reactivity of the compound (Fig. 6).

Fig. 6
figure 6

HOMO–LUMO energy diagram of 2c, 2a, 1c

The HOMO and LUMO energies of the two molecules were measured according to Koopman’s theorem, as shown in Table 8. Additionally, the energy values of the HOMO and LUMO were used to define the parameters ∆E gap (LUMO–HOMO energy), electrophilicity index (ω), electronegativity (χ), nucleophilicity index (N), global hardness (η), electron affinity (A), and ionisation energy (I), global softness (s), chemical potential (μ). These variables were calculated based on the previously mentioned equations and were connected. Because HOMO orbitals tend to give away electrons and LUMO orbitals tend to take electrons, their energies are proportional to their respective electron affinities (A) and ionisation energies (Ip). A large ∆E gap indicates an excellent stability and low chemical reactivity. ∆E gap is a measure of chemical reactivity. The results showed that 2c (∆E gap = 0.14 eV) is more chemically stable than 2a and 1c (∆E gap = 0.13 eV). Global hardness (η), chemical potential (μ),global softness (S), and are additional standards for chemical stability. Higher hardness and lower softness values indicated the stability of the compound, for example compounds 2c, 2a, and 1c (μ = 0.14 eV, η = 0.07 eV, and S = 14.3 eV). Compounds 2c, 2a, and 1c have Mulliken electronegativity (x) and Electrophilicity index (ω) values of x = 0.14 eV and ω = 0.14, respectively.

Table 8 Frontier molecular orbital energy and reactivity characteristics for 2a, 1c and 2c

Molecular electrostatic potential surface

The potential surfaces provide information on the net electrostatic effects on the overall charge distribution of the molecule. A map of the molecular electron density surface is shown in (Figs. 7, 8), where the positive side of the nucleophilic atoms is coloured blue, and the positive side of the electrophilic atoms is green. The light-blue area indicates zero potential. The reactive regions in hydrogen bonds for nucleophilic and electrophilic attacks can be precisely identified with the help of MEP, which results from the charge distribution in space around a molecule.

Fig. 7
figure 7

Electrostatic potential Map 2c, 2a and 1c

Fig. 8
figure 8

Electron density 2c, 2a and 1c


In this study, Cu(phen)Cl2 was used as a catalyst in the conversion process to create a series of Mannich-based imidazole derivatives, 1(a–f) and 2(a–e). The Cu(phen)Cl2 catalyst was highly effective and yielded a higher yield than other Cu(II) catalysts. Compound 2d (MIC: 0.25 μg/mL) was more active in S. aureus than ciprofloxacin (MIC: 0.5 μg/mL) with a molecular docking score of 1BDD protein (− 3.4 kcal/mol). The molecular docking score for compound 1c for the 1AI9 protein was (− 6.0 kcal/mol) compared to clotrimazole's (− 3.1 kcal/mol), compound 1c more effective in C. albicans (MIC = 0.25 g/mL). The molecular docking score of (− 6.1 kcal/mol) for the 3OGN protein of compound 1a, larvicidal investigations showed that compound 1a (LD50 = 34.9 g/mL) was significantly more effective than permethrin. Compounds 1a, 2d, and 1c can be considered to be the most potential compounds with larvicidal, antibacterial, and antifungal activities.

Availability of data and materials

The data and materials used in this study are entirely transparent.



Density functional theory


Ribonucleic acid


Thin-layer chromatography


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The authors extend their appreciation to the Reserchers supporting project number (RSP2023R393) King Saud University, Riyadh, Saudi Arabia.


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JM: Spectral Discussion. IA: Investigation. MG: Biological studies. AH: Methodology. AA: Compound Characterization; MS: DFT Calculation; RG: Formal analysis. All authors read and approved the final manuscript.

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Additional file 1.

Figure S1 – S24: 1H NMR, 13C NMR, FTIR, and Mass spectrum of compounds (1a-1f) Figure S25- S42: 1H NMR, 13C NMR, FTIR, and Mass spectrum of compounds (2a-2e) Figure S43- S48: 13C spectra analysis labeled compounds (1a-1f) Figure S49-S53: 13C spectra analysis labeled compounds (2a-2e) Table S1-S6: 1H spectra analysis tabulation of compounds (1a-1f) Table S7-S11: 1H spectra analysis tabulation of compounds (2a-2e).

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Mullaivendhan, J., Akbar, I., Gatasheh, M.K. et al. Cu (II)-catalyzed: synthesis of imidazole derivatives and evaluating their larvicidal, antimicrobial activities with DFT and molecular docking studies. BMC Chemistry 17, 155 (2023).

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