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Article

Design, Synthesis, and Molecular Docking of New Hydrazide–Hydrazone Derivatives with Imidazole Scaffold as Potential Antimicrobial Agents

by
Rita M. Borik
Department of Physical Sciences, Chemistry Division, College of Science, Jazan University, P.O. Box 114, Jazan 45142, Saudi Arabia
Chemistry 2025, 7(6), 172; https://doi.org/10.3390/chemistry7060172
Submission received: 24 September 2025 / Revised: 10 October 2025 / Accepted: 11 October 2025 / Published: 23 October 2025
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Abstract

The reaction of imidazole-5-carbohydrazide 1 with hydrazonyl halides 2a,b gave the corresponding hydrazide–hydrazone derivatives 3a,b. Afterwards, 3-methyl-5-(4-methyl-2-aryl-1H-imidazol-5-yl)-4-(2-phenylhydrazineylidene)-4H-pyrazole 4a,b was affordably produced by cyclizing the latter compounds 3a,b in EtOH with Et3N at reflux temperature. The corresponding piperidinyl, morpholinyl, and piperazinyl derivatives 5a–f were produced by a nucleophilic substitution reaction of 3a,b with piperidine, morpholine, and 1-methylpiperazine in EtOH at reflux temperature. The condensation reaction of carbohydrazide 1 with either 3-acetyl-2H-chromen-2-one or 1-(benzofuran-2-yl)ethan-1-one in EtOH with AcOH at reflux temperature yielded the corresponding hydrazones 6 and 7, respectively, in excellent yields. Twelve compounds were evaluated for their antibacterial properties and to ascertain their minimum inhibitory concentrations utilizing well diffusion methods. All compounds showed differing levels of antibacterial efficacy depending on the microbial species. Compounds 4b and 5c had the most favorable results, with inhibition zones of 2.7 cm against the Gram-positive bacterium S. aureus, with a minimum inhibitory concentration (MIC) of 50 µg/mL. Compounds 4b and 5c, demonstrating the highest activity, were subjected to molecular docking investigations to evaluate their inhibitory effects on the enzyme L-glutamine: D-fructose-6-phosphate amidotransferase [GlcN-6-P] of 2VF5. The molecular docking results revealed that both 4b and 5c exhibited a minimum binding energy of −8.7 kcal/mol, whereas the natural ligand GLP displayed a binding energy of −6.2 kcal/mol, indicating a substantial affinity for the active site; thus, they may be considered potent inhibitors of GlcN-6-P synthase.

Graphical Abstract

1. Introduction

There is an increasing prevalence of public health challenges attributable to antimicrobial resistance (AMR) in antibiotic therapy. Consequently, it is essential to identify a new drug that successfully confronts the issues associated with antimicrobial resistance (AMR) [1]. Historically, medications containing heterocyclic nuclei have demonstrated considerable chemotherapeutic activity and contributed to the development of novel treatments [2]. A variety of heterocyclic compounds are currently utilized in medicinal applications for the treatment of infectious disorders. Pharmaceuticals containing heterocyclic rings hold substantial importance [3].
Imidazole serves as a significant pharmacophore in drug discovery (Figure 1). Numerous commercially available medications contain the imidazole ring, including etomidate [4], phenytoin [5], miconazole [6], metronidazole [7], azathioprine [8], dacarbazine [9], tinidazole [10], and pimobendan [11], among others. In addition, compounds containing imidazole possess several medicinal activities, including antimicrobial [12], anticancer [13,14], analgesic, antifungal, antihypertensive [15], antiviral, antitumor, anti-tubercular, antihistaminic [16], anti-inflammatory [17], antidepressant [18], antioxidant [19], antidiabetic [20], anticonvulsant [21], anti-allergic [22], and antirheumatic effects [23].
On the other hand, hydrazide–hydrazones (–CO–NH–N=CH-) are of ongoing interest owing to their extensive range of biological characteristics [24,25,26,27]. Moreover, hydrazide–hydrazones are multifaceted molecules utilized in the synthesis of heterocyclic systems [24,26,28,29] and the creation of metal complexes and serve as ligands in coordination chemistry [30,31,32]. Because they hydrolyze both in vitro and in vivo to produce less toxic active metabolites than hydrazides, hydrazide–hydrazones exhibit promising efficacy in cancer therapy [33,34,35]. Hydrazide–hydrazone is a desirable alternative for prodrug production because it blocks the -NH2 group in the hydrazide linker [36,37,38,39,40,41]. Antimicrobial characteristics are the most prevalent bioactivity profiles of hydrazide–hydrazones in the scientific literature [42,43,44,45,46,47,48,49,50,51,52,53,54,55,56,57,58,59,60,61,62,63,64,65,66]. In addition, the hydrazone moiety is found in the chemical structure of antimicrobial agents, including nitrofurazone, furazolidone, and nitrofurantoin [26] (Figure 2). GlcN-6-P synthase catalyzes the first committed step in amino–sugar (cell wall precursor) biosynthesis in bacteria and fungi, so inhibiting it can block cell-wall formation and bacterial/fungal growth [67]. Inhibiting this enzyme blocks the production of these essential cell wall precursors, leading to cell wall deficiencies and ultimately causing bacterial or fungal cell death. This makes GlcN-6-P synthase a promising target for the development of novel antibacterial and antifungal drugs, as its inhibition is lethal to these microbes but not to mammalian cells [68]. Despite decades of research, the development of effective, safe, and orally active drugs targeting specific enzymes remains challenging. To overcome this, strategies include using prodrugs for better uptake, designing covalent or transition-state mimic inhibitors to increase binding, targeting allosteric sites for novel inhibition, employing fragment-based and structure-guided drug design for optimization, and for regulatory purposes, targeting the glmS riboswitch, which senses the metabolite GlcN-6-P [69]. In the present work, we aimed to design and synthesize new inhibitors for GlcN-6-P synthase using PDB hits (2VF5) as a template.
In consideration of the previously mentioned benefits and in alignment with my research [70,71,72,73], I introduce the synthesis of an innovative library of hydrazide–hydrazone derivatives featuring imidazole, piperidinyl, morpholinyl, piperazinyl, benzofuran, and coumarin moieties derived from 4-methyl-2-phenyl-1H-imidazole-5-carbohydrazide 1, along with an evaluation of their antibacterial properties.

2. Experimental Section

2.1. General Information

All the chemicals required for the synthesis and other experimental work were purchased Sigma Aldrich chemical companies (Sigma-Aldrich, Burlington, MA, USA). Melting points were uncorrected and measured using a digital Gallen-Kamp MFB-595 device (Gallenkamp, London, UK). Using KBr pellets, IR spectra were acquired using a Shimadzu FTIR 440 spectrometer (Shimadzu, Kyoto, Japan). The data were analyzed with an MS-50 Kratos (A.E.I.) spectrometer (Kratos, Manchester, UK), which was used to obtain mass spectra at 70 eV. Using DMSO-d6 (≥99.8%, Sigma-Aldrich, Burlington, MA, USA) as an internal standard and TMS (≥99.8%, Sigma-Aldrich, Burlington, MA, USA) as an external standard, 1H NMR (500 MHz) and 13C NMR (125 MHz) spectra were acquired on a Bruker model UltraShield NMR spectrometer (Bruker Biospin GmbH, Rheinstetten, Germany). The units used to report chemical changes are δ ppm. Thin-layer chromatography (TLC) was used to assess the homogeneity of the products and the course of the reactions.

2.2. Synthesis

Synthesis of compounds 3a and 3b
A mixture of 4-methyl-2-phenyl-1H-imidazole-5-carbohydrazide 1 (2.16 g, 10 mmol, [74]) and 2-oxo-N-(p-tolyl)propanehydrazonoyl chloride 2a or N-(4-chlorophenyl)-2-oxopropanehydrazonoyl chloride 2b (10 mmol) in absolute ethanol (20 mL, Sigma-Aldrich, Burlington, MA, USA) was subjected to reflux for 2–3 h. The reaction mixture was allowed to cool to ambient temperatures. The isolated crystals were filtered to yield compounds 3a and 3b, respectively.
2-(2-(4-Methyl-2-phenyl-1H-imidazole-5-carbonyl)hydrazineylidene)-N-(p-tolyl)propanehydrazonoyl chloride (3a). Yield: 87%; Color: light brown; m.p. 245–246 °C; IR (KBr, υmax, cm−1): 3334–3306 cm−1 (3NH), 1682 (C=O), 1661 (C=N); δ 12.96 (s, 1H, NH-imidazole, D2O exchangeable), 10.39 (s, 1H, NH, D2O exchangeable), 10.05 (s, 1H, NH, D2O exchangeable), 7.99 (d, J = 7.5 Hz, 2H, Ar-H), 7.54–7.38 (m, 3H, Ar-H), 7.24 (d, J = 8.0 Hz, 2H, Ar-H), 7.11 (d, J = 8.0 Hz, 2H, Ar-H), 2.59 (s, 3H, Me), 2.39 (s, 3H, Me), 2.25 (s, 3H, Me); 13C NMR (125 MHz, DMSO-d6): δ 159.08, 146.46, 144.13, 141.77, 134.87, 130.28, 130.05, 129.93, 129.35, 129.29, 128.78, 125.60, 123.72, 114.21, 20.78, 12.79, 11.14; EI-MS 408 [M+, 10%], 410 [M+ + 2, 5%]; Anal. Calcd. for C21H21ClN6O: C, 61.69; H, 5.18; N, 20.55; Found: C, 61.58; H, 5.06; N, 20.33.
N-(4-chlorophenyl)-2-(2-(4-methyl-2-phenyl-1H-imidazole-5-carbonyl)hydrazineylidene)propanehydrazonoyl chloride (3b). Yield: 82%; Color: yellow; m.p. 232–233 °C; IR (KBr, υmax, cm−1): 3343–3164 cm−1 (3NH), 1640 (C=O), 1598 (C=N); 1HNMR (500 MHz, DMSO-d6): δ 13.08 (s, 1H, NH-imidazole, D2O exchangeable), 10.46 (s, 1H, NH, D2O exchangeable), 10.29 (s, 1H, NH, D2O exchangeable), 8.02 (d, J = 7.5 Hz, 2H, Ar-H), 7.52 (m, 3H, Ar-H), 7.35 (dd, J = 8, 3.0 Hz, 4H, Ar-H), 2.51 (s, 3H, Me), 2.40 (s, 3H, Me); 13C NMR (125 MHz, DMSO-d6): δ 158.94 (CO), 154.32, 146.44, 144.12, 143.04, 135.25, 129.46, 129.40, 128.83, 125.79, 125.15, 125.02, 116.32, 115.77, 12.94, 11.24; EI-MS 428 [M+, 15%], 430 [M+ + 2, 8%]; Anal. Calcd. for C20H18Cl2N6O: C, 55.96; H, 4.23; N, 19.58; Found: C, 55.84; H, 4.06; N, 19.39.
Synthesis of compounds 4a and 4b
Compound 3a or 3b (1 mmol) was refluxed in ethanol (20 mL, Sigma-Aldrich, Burlington, MA, USA) in the presence of drops of TEA (99.5%, Sigma-Aldrich, Burlington, MA, USA) for 2 h, then allowed to cool and filtered to obtain compounds 4a and 4b, respectively.
3-Methyl-5-(4-methyl-2-phenyl-1H-imidazol-5-yl)-4-(2-(p-tolyl)hydrazineylidene)-4H-pyrazole (4a). Yield: 89%; Color: light brown; m.p. 181–182 °C; IR (KBr, υmax, cm−1): IR (KBr, υmax, cm−1): 3306, 3350, cm−1 (2NH), 1594 (C=N); 1HNMR (500 MHz, DMSO-d6): δ 12.97 (s, 1H, NH-imidazole, D2O exchangeable), 10.04 (s, 1H, NH, D2O exchangeable), 8.01 (m, 2H, Ar-H), 7.54–7.38 (m, 3H, Ar-H), 7.26–7.19 (m, 2H, Ar-H), 6.99–6.91 (m, 2H, Ar-H), 2.60 (s, 3H, Me), 2.39 (s, 3H, Me), 2.18 (s, 3H, Me); 13C NMR (125 MHz, DMSO-d6): δ 147.35, 147.19, 143.59, 129.96, 129.71, 129.54, 129.38, 129.35, 129.17, 125.62, 125.44, 114.20, 114.11, 112.98, 20.54, 15.97, 14.71; EI-MS 356 [M+, 20%], 357 [M+ + 1, 5%]; Anal. Calcd. for C21H20N6: C, 70.77; H, 5.66; N, 23.58; Found: C, 70.65; H, 5.50; N, 23.40.
4-(2-(4-Chlorophenyl)hydrazineylidene)-3-methyl-5-(4-methyl-2-phenyl-1H-imidazol-5-yl)-4H-pyrazole (4b). Yield: 90%; Color: orange; m.p. 179–180 °C; IR (KBr, υmax, cm−1): 3340, 3310 cm−1 (2NH), 1577 (C=N); 1HNMR (500 MHz, DMSO-d6): δ 13.18 (s, 1H, NH-imidazole, D2O exchangeable), 11.05 (s, 1H, NH, D2O exchangeable), 8.00 (d, J = 7.5 Hz, 2H, Ar-H), 7.53 (m, 3H, Ar-H), 7.28 (d, J = 8 Hz, 2H, Ar-H), 7.19 (d, J = 8 Hz, 2H, Ar-H), 2.61 (s, 3H, Me), 2.26 (s, 3H, Me); 13C NMR (125 MHz, DMSO-d6): δ 153.71, 151.18, 145.69, 144.17, 135.64, 130.99, 129.55, 129.46, 129.33, 126.64, 126.49, 125.84, 123.43, 114.63, 18.00, 15.82; EI-MS 357 [M+, 25%], 359 [M+ + 2, 7%]; Anal. Calcd. for C20H17ClN6: C, 63.74; H, 4.55; N, 22.30; Found: C, 63.61; H, 4.42; N, 22.18.
Synthesis of compounds 5a–f
A mixture of compound 3a or 3b (1 mmol) and an appropriate amine, piperidine, morpholine, or N-methyl piperazine (1 mmol, 99%, Sigma-Aldrich, Burlington, MA, USA) in absolute ethanol (20 mL, 99%, Sigma-Aldrich, Burlington, MA, USA) and a few drops of TEA (0.3 mL,99.5%, Sigma-Aldrich, Burlington, MA, USA) was subjected to reflux for 2–3 h. The reaction mixture was allowed to cool to ambient temperatures. The isolated crystals were filtered to yield compounds 5a–f, respectively.
4-Methyl-2-phenyl-N’-(-1-(piperidin-1-yl)-1-(2-(p-tolyl)hydrazineylidene)propan-2-ylidene)-1H-imidazole-5-carbohydrazide (5a). Yield: 80%; Color: dark yellow; m.p. 180 °C; IR (KBr, υmax, cm−1): 3310–3180 (3NH), 1676 (C=O), 1566 (C=N); 1HNMR (500 MHz, DMSO-d6): δ 12.33 (s, 1H, NH-imidazole, D2O exchangeable), 12.00 (s, 1H, NH, D2O exchangeable), 10.34 (s, 1H, NH, D2O exchangeable), 8.21–8.14 (m, 2H, Ar-H), 7.54–7.44 (m, 3H, Ar-H), 7.33–7.27 (m, 2H, Ar-H), 7.11–7.06 (m, 2H, Ar-H), 3.41–3.35 (m, 4H, piperidinyl-H), 2.58 (s, 3H, Me), 2.36 (s, 3H, Me), 2.22 (s, 3H, Me), 1.66 (m, 4H, piperidinyl-H), 1.62–1.54 (m, 2H, piperidinyl-H); 13C NMR (125 MHz, DMSO-d6): δ 159.18, 148.84, 147.80, 141.74, 139.35, 135.15, 134.52, 132.07, 130.29, 129.97, 129.81, 129.02, 127.72, 114.01, 49.23, 25.63, 24.31, 20.73, 14.88, 14.38; EI-MS 443 [M+, 33%]; Anal. Calcd. for C25H29N7O: C, 67.70; H, 6.59; N, 22.11; Found: C, 67.58; H, 6.50; N, 22.03.
4-methyl-N’-(-1-morpholino-1-(2-(p-tolyl)hydrazineylidene)propan-2-ylidene)-2-phenyl-1H-imidazole-5-carbohydrazide (5b). Yield: 81%; Color: light brown; m.p. 200 °C; IR (KBr, υmax, cm−1): 3330–3200 (3NH), 1671 (C=O), 1536 (C=N); 1HNMR (500 MHz, DMSO-d6): δ 12.64 (s, 1H, NH-imidazole, D2O exchangeable), 12.41 (s, 1H, NH, D2O exchangeable), 9.86 (s, 1H, D2O exchangeable), 7.91 (m, 2H, Ar-H), 7.52–7.39 (m, 3H, Ar-H), 7.34 (m, 2H, Ar-H), 7.19–7.09 (m, 2H, Ar-H), 3.82–3.76 (m, 4H, morpholinyl-H), 3.73 (t, J = 4.8 Hz, 2H, morpholinyl-H), 3.67 (t, J = 4.8 Hz, 2H, morpholinyl-H), 2.92 (s, 3H, Me), 2.33 (s, 3H, Me), 2.24 (s, 3H, Me); 13C NMR (125 MHz, DMSO-d6): δ 166.03, 154.21, 152.33, 144.96, 144.62, 138.08, 130.79, 130.06, 129.98, 129.72, 129.38, 129.26, 125.33, 114.91, 66.62, 48.13, 20.54, 14.57, 13.78; EI-MS 445 [M+, 20%]; Anal. Calcd. for C24H27N7O2: C, 64.70; H, 6.11; N, 22.01; Found: C, 64.60; H, 6.00; N, 21.88.
4-methyl-N’-(-1-(4-methylpiperazin-1-yl)-1-(2-(p-tolyl)hydrazineylidene)propan-2-ylidene)-2-phenyl-1H-imidazole-5-carbohydrazide (5c). Yield: 82%; Color: light brown; m.p. 183 °C; IR (KBr, υmax, cm−1): 3310–3220 (3NH), 1665 (C=O), 1596 (C=N); 1HNMR (500 MHz, DMSO-d6): δ 13.11 (s, 1H, NH-imidazole, D2O exchangeable), 11.65 (s, 1H, NH, D2O exchangeable), 10.41 (s, 1H, NH, D2O exchangeable), 8.02 (m, 2H, Ar-H), 7.55–7.42 (m, 3H, Ar-H), 7.30–7.18 (m, 2H, Ar-H), 7.16–7.08 (m, 2H, Ar-H), 2.66–2.58 (m, 4H, piperazinyl-H), 2.54 (s, 3H), 2.45 (s, 3H, Me), 2.29 (s, 3H, Me), 2.27–2.18 (m, 4H, piperazinyl-H), 2.16 (s, 3H, Me); 13C NMR (125 MHz, DMSO-d6) δ (ppm): 166.81, 152.50, 151.66, 144.13, 143.58, 130.05, 129.93, 129.70, 129.53, 129.35, 125.61, 125.44, 114.22, 112.63, 54.03, 47.41, 45.76, 20.57, 14.20, 12.78; EI-MS 472 [M+, 25%]; Anal. Calcd. for C26H32N8O: C, 66.08; H, 6.83; N, 23.71; Found: C, 65.89; H, 6.71; N, 23.61.
N’-(-1-(2-(4-chlorophenyl)hydrazineylidene)-1-(piperidin-1-yl)propan-2-ylidene)-4-methyl-2-phenyl-1H-imidazole-5-carbohydrazide (5d). Yield: 85%; Color: yellow; m.p. 185–186 °C; IR (KBr, υmax, cm−1): 3350–3230 (3NH), 1672 (C=O), 1596 (C=N); 1HNMR (500 MHz, DMSO-d6): δ 12.95 (s, 1H, NH-imidazole, D2O exchangeable), 10.03 (s, 1H, D2O exchangeable), 9.78 (s, 1H, D2O exchangeable), 8.06–8.00 (m, 2H, Ar-H), 7.49–7.33 (m, 5H, Ar-H), 7.23–7.18 (m, 2H, Ar-H), 3.02–2.87 (m, 4H, Piperidinyl-H), 2.62 (s, 3H, Me), 2.21 (s, 3H, Me), 1.69–1.56 (m, 4H, Piperidinyl-H), 1.33 (m, 2H, Piperidinyl-H); 13C NMR (125 MHz, DMSO-d6): δ 158 (CO), 152.65, 151.94, 145.34, 144.68, 142.87, 133.97, 129.95, 129.34, 129.27, 129.12, 128.93, 125.39, 116.32, 49.07, 25.79, 24.42, 14.76, 13.77; EI-MS 477 [M+, 30%], 479 [M+ + 2, 11%]; Anal. Calcd. for C25H28ClN7O: C, 62.82; H, 5.90; N, 20.51; Found: C, 62.69; H, 5.69; N, 20.39.
N’-(-1-(2-(4-chlorophenyl)hydrazineylidene)-1-morpholinopropan-2-ylidene)-4-methyl-2-phenyl-1H-imidazole-5-carbohydrazide (5e). Yield: 82%; Color: yellow; m.p. 190–191 °C; IR (KBr, υmax, cm−1): 3306–3212 (3NH), 1681 (C=O), 1549 (C=N); 1HNMR (500 MHz, DMSO-d6): δ 12.32 (s, 1H, NH-imidazole, D2O exchangeable), 11.23 (s, 1H, NH, D2O exchangeable), 10.37 (s, 1H, NH, D2O exchangeable), 8.21–8.15 (m, 2H, Ar-H), 7.54–7.44 (m, 3H, Ar-H), 7.28–7.23 (m, 2H, Ar-H), 7.18–7.12 (m, 2H, Ar-H), 3.66 (m, 4H, morpholinyl-H), 3.60 (m, 4H, morpholinyl-H), 2.87 (s, 3H, Me), 2.39 (s, 3H, Me); 13C NMR (125 MHz, DMSO-d6): δ 159.18 (CO), 148.08, 147.80, 143.47, 139.42, 135.15, 134.52, 130.29, 129.97, 129.43, 129.02, 127.72, 127.04, 116.25, 66.43, 48.51, 14.88, 14.38; EI-MS 479 [M+, 22%], 481 [M+ + 2, 7%]; Anal. Calcd. for C24H26ClN7O2: C, 60.06; H, 5.46; N, 20.43; Found: C, 59.89; H, 5.35; N, 20.35.
N’-(-1-(2-(4-chlorophenyl)hydrazineylidene)-1-(4-methylpiperazin-1-yl)propan-2-ylidene)-4-methyl-2-phenyl-1H-imidazole-5-carbohydrazide (5f). Yield: 83%; Color: yellow; m.p. 203 °C; IR (KBr, υmax, cm−1): 3360–3252 (3NH), 1675 (C=O), 1553 (C=N); 1HNMR (500 MHz, DMSO-d6): δ 12.95 (s, 1H, NH-imidazole, D2O exchangeable), 10.99 (s, 1H, NH, D2O exchangeable), 10.63 (s, 1H, NH, D2O exchangeable), 8.02–7.94 (m, 2H, Ar-H), 7.47–7.38 (m, 3H, Ar-H), 7.24–7.16 (m, 2H, Ar-H), 7.01–6.95 (m, 2H, Ar-H), 2.99 (s, 3H, Me), 2.63–2.53 (m, 4H, piperazinyl-H), 2.42 (s, 3H, Me), 2.29–2.15 (m, 7H, piperazinyl-H& Me); 13C NMR (125 MHz, DMSO-d6): δ 158.04, 152.67, 145.53, 143.08, 140.64, 134.74, 131.98, 129.35, 129.29, 129.25, 129.19, 129.14, 128.95, 115.69, 54.80, 48.45, 46.27, 14.80, 11.07; EI-MS 492 [M+, 17%], 494 [M+ + 2, 6%]; Anal. Calcd. for C25H29ClN8O: C, 60.91; H, 5.93; N, 22.73; Found: C, 60.78; H, 5.80; N, 22.59.
Synthesis of coumarin and benzofuran derivatives 6 and 7
A mixture of compound 1 (1 mmol) and either 3-acetylcoumarin or 2-acetylbenzofuran (1 mmol) in absolute ethanol (20 mL) and a few drops of AcOH (0.3 mL) was subjected to reflux for 1–2 h. The reaction mixture was allowed to cool to ambient temperatures. The isolated crystals were filtered to provide compounds 6 and 7, respectively.
4-Methyl-N’-(1-(2-oxo-2H-chromen-3-yl)ethylidene)-2-phenyl-1H-imidazole-5-carbohydrazide (6). Yield: 91%; Color: light yellow; m.p. 270–271 °C; IR (KBr, υmax, cm−1): 3290–3044 (2NH), 1700 (C=O), 1661 (C=O), 1609 (C=N); 1HNMR (500 MHz, DMSO-d6): δ 11.48 (s, 1H, NH-imidazole, D2O exchangeable), 10.84 (s, 1H, NH, D2O exchangeable), 8.17 (s, 1H, quinolone-H), 8.05–7.93 (m, 2H, quinolone-H), 7.68 (t, J = 8.0 Hz, 1H, Ph-H), 7.59 (m, 2H, quinolone-H), 7.53–7.39 (m, 4H, Ph-H), 2.62 (s, 3H, Me), 2.41 (s, 3H, Me); 13C NMR (125 MHz, DMSO-d6): δ 158.05 (CO), 155.08 (CO), 153.66, 147.52, 144.76, 143.71, 134.96, 131.25, 129.76, 129.63, 129.38, 125.93, 125.42, 125.38, 124.93, 119.26, 118.65, 116.54, 19.03, 11.13; EI-MS 386 [M+, 40%]; Anal. Calcd. for C22H18N4O3: C, 68.38; H, 4.70; N, 14.50; Found: C, 68.25; H, 4.65; N, 14.43.
4-Methyl-N’-(1-(2-oxo-2H-chromen-3-yl)ethylidene)-2-phenyl-1H-imidazole-5-carbohydrazide (7). Yield: 92%; Color: off-white; m.p. 272–273 °C; IR (KBr, υmax, cm−1): 3280–3039 (2NH), 1651 (C=O), 1602 (C=N); 1HNMR (500 MHz, DMSO-d6): δ 11.62 (s, 1H, NH-imidazole, D2O exchangeable), 11.13 (s, 1H, NH, D2O exchangeable), 8.09 (m, 2H, benzofuran-H), 7.74–7.34 (m, 6H, Ph-H& benzofuran-H), 7.32–7.25 (m, 2H, benzofuran-H), 2.63 (s, 3H, Me), 2.57 (s, 3H, Me); 13C NMR (125 MHz, DMSO-d6): δ 155.08 (CO), 147.52, 144.76, 143.71, 134.96, 131.25, 129.76, 129.63, 129.38, 125.93, 125.42, 125.38, 124.93, 119.26, 118.65, 116.59, 116.54, 19.03, 11.13; EI-MS 358 [M+, 35%]; Anal. Calcd. for C21H18N4O2: C, 70.38; H, 5.06; N, 15.63; Found: C, 70.29; H, 4.95; N, 15.51.

2.3. Antimicrobial Evaluation

Antibacterial activities of the synthesized compounds were evaluated using the well diffusion method. Mueller–Hinton agar (MHA, 99%, BioLife co., Milano, Italy) and potato dextrose agar (99%, BioLife co., Milano, Italy) were used as media for bacterial and fungal species, respectively. The inhibition zones were expressed in centimeters (cm). Staphylococcus aureus (ATCC 25923, ATCC, Virginia, USA), Pseudomonas aeruginosa (ATCC 25619, ATCC, Virginia, USA), and Escherichia coli (ATCC 25922, ATCC, Virginia, USA) were used as references for the antibacterial assay, while Candida albicans and Rhizopus racemosus were locally isolated strains. Plates of MHA agar were inoculated with bacterial strains, and PDA was inoculated with the fungal strains suspensions (1.5 × 106 CFU/mL), and wells of 6 mm diameter were filled with 50 µL containing 300 µg from the test samples. The plates were incubated at suitable temperatures according to the type of microorganism for 24 h. After the incubation period, the diameter of the growth inhibition zones was measured. Amikacin (30 µg, Sigma-Aldrich co., Melbourne, Australia) and neomycin (10 µg, Sigma-Aldrich co., Melbourne, Australia) were used as reference antimicrobial agents for bacteria and fungi, respectively.

2.4. Minimum Inhibitory Concentration

To determine MIC values, all quantitative methods use the Mueller–Hinton (MH) medium (99%, BioLife co., Milano, Italy), either in the form of agar (MHA, 99%, BioLife co., Milano, Italy). Concentrations of the antimicrobial agents 50, 100, 150, 200, 300, and 400 µg were prepared in DMSO (99%, Fisher Scientific co., Weil am Rhein, Germany). Aliquots of 50 µL from the sample were placed in 6 mm wells in the seeded agar plate. The inoculum size was adjusted to 1.6 × 106 cfu. The plates were incubated at 30 °C for 24 and 48 h. At the end of the incubation periods, the inhibition zone was measured to determine the MIC.

2.5. Statistical Analysis

All results were taken as the mean of triplicates, and SD ± was calculated.

2.6. Molecular Docking

A molecular docking study of compounds under investigation (4b and 5c) together with the crystal structure of the glucosamine-6-phosphate of GlcN-6-P synthase as obtained from PDB with ID 2VF5 (1.9 Å resolution) was performed using PyRx tools Autodock Vina (version 1.1.2, PyRx—Python Prescription, USA) [75,76,77,78,79]. Amino acid residues of the active pocket of the glucosamine-6-phosphate of GlcN-6-P synthase are THR302, CYS300, THR352, GLN348, SER303, SER349, VAL399, and ALA602, which would be considered the most accurate active region, as it is solved by experimental crystallographic data [80]. The co-crystallized ligand (GLP) was re-docked in the enzyme’s active pocket to validate the molecular docking technique. It was noticed that the re-docked native ligand showed a docking score (S) of −6.2 kcal/mol and re-created all the key interactions with the active amino acid residues of the active pocket through hydrogen bond interactions. The native ligand and the water molecules were removed from the original protein using the VEGA ZZ 2.3.2 tool (Version 2.3.2, https://www.ddl.unimi.it/cms/index.php?Software_projects:VEGA_ZZ) (accessed on 14 September 2025), followed by adding polar hydrogen and Kollman charges, and then converted to PDBQT format by Autodock Vina tools. In Autodock Vina software (Version 1.1.2, PyRx—Python Prescription, USA), the search algorithm was used for active molecules. The Lamarckian genetic algorithm (LGA) was employed to obtain the best binding site. Designed compounds are saved as a mol file, then protonated, minimized, and converted to a pdb file by Open Babel software (Version 2.3). The Gasteiger partial charges were added to the atoms of the ligand, and rotatable bonds were defined and then converted to pdbqt format by Autodock tools. AutoGrid was used with a grid box to create the grid map. The grid box center was 32.00 × 19.72 × −3.14 Å. The ten docked poses were generated for each compound and ranked according to the binding energy. The pose of lowest binding energy and zero Å root-mean-square deviation (RMSD) was considered the fittest and most complex with the receptor for analysis. The molecular interactions and binding modes of the top poses were visually examined using BIOVIA Discovery Studio 2021 (Version 2021, The 3DEXPERIENCE Company).

3. Results

3.1. Chemistry

4-Methyl-2-phenyl-1H-imidazole-5-carbohydrazide 1 was synthesized from the respective carboxylic acid using hydrazine hydrate [74]. Hydrazide 1 was reacted with hydrazonyl halides 2a and 2b in ethanol at reflux temperature to obtain the corresponding hydrazide–hydrazones 3a and 3b with yields of 87% and 82%, respectively. Subsequently, cyclization of hydrazide–hydrazones 3a,b in EtOH with Et3N at reflux temperature gave 3-methyl-5-(4-methyl-2-aryl-1H-imidazol-5-yl)-4-(2-phenylhydrazineylidene)-4H-pyrazole 4a,b in excellent yields (Scheme 1). The structure of compounds 3 was identified based on elemental analyses and spectral data. The IR spectra of 3a indicated the absence of the NH2 group and exhibited discrete absorption bands corresponding to functional groups 3NH at 3334–3306 cm−1, C=O at 1682 cm−1, and C=N at 1661 cm−1. The 1H NMR spectra of 3a exhibited three D2O exchangeable singlet signals at δ 12.96, 10.39, and 10.05 ppm. Additionally, there are three doublet signals and one multiplet signal from the aromatic protons, exhibiting chemical shifts of δ 7.99–7.11 ppm. Furthermore, protons of three methyl groups were observed at δ 2.59, 2.39, and 2.25 ppm as singlet signals. The 13C NMR spectra exhibited 17 signals. The most important signals resonate at δ 11.14 (Me), 12.79 (Me), 20.78 (Me), and 159.08 (C=O). The mass spectrum displayed a [M+] ion peak at m/z 408 (10%).
The IR spectrum of 4a exhibited the absence of a carbonyl group and presented discrete absorption bands corresponding to two NH and C=N functional groups at 3306, 3350, and 1594 cm−1, respectively. The 1H NMR spectra of 4a exhibited two D2O exchangeable singlet signals at δ 12.97 and 10.04 ppm. The 13C NMR spectrum exhibited 17 signals and did not contain the carbonyl functionality. The mass spectrum displayed a [M+] ion peak at m/z 356 (5%).
The nucleophilic substitution reaction of compounds 3a and 3b with piperidine, morpholine, and 1-methylpiperazine occurred in ethanol with triethylamine at reflux temperature, yielding the corresponding piperidinyl derivatives 5a and 5d, morpholinyl derivatives 5b and 5e, and piperazinyl derivatives 5c and 5f, respectively (Scheme 2). The 1H NMR spectra of 5b displayed one multiplet signal and two triplet signals at δ 3.82–3.76, 3.73, and 3.67 ppm, attributed to morpholinyl protons, alongside the original protons of compound 3a, indicating the substitution of the chlorine atom with morpholine. The 13C NMR exhibited 19 signals. The principal signals are observed at δ 66.62 (CH2, morpholine), 48.13 (CH2, morpholine), and 166.03 (C=O). The mass spectrum exhibited a [M+] ion peak at m/z 445 (12%).
Condensation reaction of hydrazide 1 with either 3-acetyl-2H-chromen-2-one or 1-(benzofuran-2-yl)ethan-1-one in EtOH with AcOH at reflux temperature yielded 4-methyl-N’-(1-(2-oxo-2H-chromen-3-yl)ethylidene)-2-phenyl-1H-imidazole-5-carbohydrazide 6 and N’-(1-(benzofuran-2-yl)ethylidene)-4-methyl-2-phenyl-1H-imidazole-5-carbohydrazide 7, respectively, in excellent yields (Scheme 3). The structure of hydrazones 6 and 7 was identified based on elemental analyses and spectral data as described in the experimental section (Supplementary Materials).

3.2. Antimicrobial Activities

Nearly all the tested compounds showed antimicrobial activities to various degrees (Table 1). It was found that the compounds 4b, 5b, and 5c have the best antimicrobial activities against the Gram-negative bacteria E. coli with the size of inhibition zones ranging from 1.7 to 2.0 cm being recorded, while the other compounds showed lower values for the inhibition zones. The activity was noticed against another Gram-negative bacterium, P. aeruginosa, where compounds 4b, 5b, 5e, and 6 recorded the best activities by zone 2.2, 2.0, 2.0, and 2.0 cm, respectively. On the other hand, compounds 4a, 4b, 5a, 5b, 5c, 5d, and 5f recorded values of inhibition zones within the range of 2.0 to 2.7 cm against the Gram-positive bacterium S. aureus. Compounds 5c and 5d achieved the best results by inhibition zone 2.7, and this was the highest value among the other compounds. Additionally, the antifungal activities of these compounds were tested against C. albicans (yeast fungi) and Rhizopus racemosus (filamentous fungi). Only two compounds, 3a and 3b, showed weak antifungal activities against C. albicans, while all other compounds had no activities, whereas compounds 3a, 3b, 5b, 5e, and 5f showed inhibition zones of diameter 1.2, 1.1, 1.4, 1.1, and 1.2 cm against the filamentous fungus R. racemosus. The other compounds had no similar activities against R. racemosus. The twelve compounds had superior antibacterial activity against both Gram-positive and Gram-negative bacteria compared to their antifungal efficacy against yeast and filamentous fungi, with a greater impact observed on filamentous fungi than on yeast.
For the determination of the minimum inhibitory concentration for the active compounds, different concentrations between 50 and 400 µg/mL were tested against five microbial strains of bacteria and fungi, as shown in Table 2. The compounds 4b and 5a had the lowest MIC, which is 50 µg/mL, especially against the G + ve bacteria S. aureus. The compounds may give larger inhibition zones at high concentrations of 400 µg/mL, but the work aimed at the lower MIC. Most of the compounds showed an MIC at 300 µg, but some compounds also showed lower MICs, like 3a, which has an MIC equal to 150 µg/mL against P. aeruginosa, and 5e, which has an MIC of 150 and 100 µg/mL against P. aeruginosa and S. aureus, respectively. Generally, the lowest MIC was 50 µg/mL. The observed antimicrobial activity may be attributed to the presence of nitrogen incorporated in the rings. Some literature attributed the biological activities to the presence of nitrogen in the ring system of these compounds, and the heterocyclic compounds with the hydrazone moiety usually exhibited good antimicrobial activities [42,43,44,45,46,47,48,49,50,51,52,53,54,55,56,57,58,59,60,61,62,63,64,65,66]. Polović et al., in 2019 [50], synthesized novel hydrazide–hydrazones of nicotinic acid and assessed their antibacterial activity. Antibacterial results showed that the compounds with a nitro group displayed good inhibition of bacterial growth; in contrast, compounds without an electron-withdrawing group (chloro-and nitro-) showed weak antibacterial activity. The authors mentioned that electron-withdrawing substituents increase the lipophilicity of the compounds, and this leads to higher partitioning of such compounds into the lipophilic phase of a microbial membrane [81].
Olayinka et al. synthesized a series of new hydrazide–hydrazones of 2-propylquinoline-4-carboxylic acid and tested antibacterial activity against six bacterial strains (P. aeruginosa, S. aureus, E. coli, Proteus vulgaris, Bacillus licheniformis, and Micrococcus varians) [45]. The authors proved that the presence of an electron-donating group (EDG) and an electron-withdrawing group (EWG) in the phenyl ring had a crucial effect on the antibacterial activity [44].
Substituting a hydrazide–hydrazone scaffold with chlorine, piperidinyl, morpholinyl, piperazinyl, 2-oxochromenyl, and benzofuranyl moieties can affect the antimicrobial activity. The specific effect depends on the molecule structure, the position of the substituent, and the type of microbe under the effect’s target.
In general, a substituent influences antimicrobial activity by altering the compound’s effect in different ways. It affects the electron density; electron-withdrawing groups (EWGs) and electron-donating groups (EDGs) affect the molecule’s electronic properties, influencing its ability to interact with microbial targets. It also affects lipophilicity, the balance between lipophilic (fat-soluble) and hydrophilic (water-soluble) character, which is crucial for a compound to cross microbial cell membranes and reach its site of action. In addition to the effect on the steric hindrance, the size and shape of a substituent can affect how a molecule fits into the active site of a microbial enzyme or receptor [26,42,82,83,84].

3.3. Molecular Docking

Based on the in vitro antimicrobial findings, it was considered beneficial to perform a molecular docking investigation against GlcN-6-P synthase of the most potent compounds, 4b and 5c, utilizing PyRx tools Autodock Vina (Version 1.1.2). GlcN-6-P synthase was identified as a target receptor due to its necessity in bacteria and fungi for the manufacture of peptidoglycan and chitin, respectively, rendering it a target for antimicrobial drugs [85]. The crystal structure of GlcN-6-P synthase (PDB ID: 2VF5, a bacterial protein of E. coli) was acquired from the Protein Data Bank (https://www.rcsb.org/structure/2VF5) (accessed on 14 September 2025). The native ligand, glucosamine-6-phosphate (GLP), served as a reference for validating the simulation procedure and establishing the dimensions and location of the grid box.
The active pocket was identified as the location of GLP complexes in GlcN-6-P of 2VF5, comprising 12 amino acid residues, ALA602, VAL399, ALA400, GLY301, THR302, SER303, CYS300, GLN348, SER349, THR352, SER347, and LYS603, as shown by Vijesh et al. [80].
The co-crystallized ligand (GLP) was re-docked into the enzyme’s active site to validate the molecular docking methodology. The re-docked native ligand exhibited a docking score (S) of −6.2 kcal/mol and successfully re-established all critical contacts with the active amino acid residues in the active pocket via hydrogen bonding.
The docking results for compounds 4b and 5c demonstrated an effective binding mode within the active pocket of the GlcN-6-P synthase crystal structure, both exhibiting a binding energy of −8.7 Kcal/mol, which is better than the binding energy of the native ligand of −6.2 kcal/mol (Table 3). Compound 4b engaged with THR302 and GLN348 (two amino acids within the receptor’s active pocket) through typical hydrogen and carbon–hydrogen interactions (Figure 3a,b). Compound 5c exhibited strong interactions with the most active amino acid residues, similar to the native ligand (Figure 3c,d). Compound 5c engaged with the active site of GlcN-6-P synthase through hydrophilic interactions with SER401, ALA602, LYS603, and ALA400, in addition to unique pi-sulfur interactions with the amino acid residue CYS300 (Table 3).
It is worth noting that compound 5c outperforms compound 4b in the number and diversity of interactions with the active amino acid residue of GlcN-6-P synthase, as it includes the hydrogen bond SER401 as well as a notable sulfur–π interaction with CYS300. Additionally, salt-bridge/electrostatic contact is observed involving LYS603.
Compound 5c likely outperforms the native sugar-phosphate ligand by combining targeted hydrogen bonding (SER401/backbone), an ionic contact with LYS603, and an extra sulfur–π interaction to CYS300, giving greater enthalpic complementarity, steric blockade of catalytic geometry, and improved cell permeability relative to a charged native substrate, all of which translate into stronger, longer-lived inhibition.
Based on molecular docking results, the mechanistic reasons why compound 5c is a better inhibitor than the native ligand (sugar phosphate) of GlcN-6-P synthase (PDB ID: 2VF5, a bacterial protein of E. coli) are as follows:
1.
It replaces a highly polar substrate with a more drug-like, better-fitting ligand:
○
The native ligand is highly polar and carries a phosphate group, which results in high enzyme binding but poor cell permeability and often rapid turnover.
○
Compound 5c lacks a full phosphate but forms multiple non-polar and aromatic interactions (p-tolyl, imidazole, piperazine) plus targeted H-bonds—this yields strong complementary packing and van der Waals enthalpy without the liability of a charged phosphate. This can produce higher apparent affinity in cell assays (better uptake and enhanced enzyme binding).
2.
There are additional enthalpic contacts beyond the substrate:
○
Compound 5c formed H-bonds to SER401 and backbone atoms around ALA400/ALA602, mimicking some substrate H-bonding, and also formed an electrostatic/salt-bridge contact with LYS603. The combination of H-bonds and ionic contact often gives stronger binding energy than the native pattern alone.
3.
The sulfur–π interaction with CYS300 is an extra interaction, while the sugar cannot make it. Sulfur–π interactions can contribute appreciably (0.5–2 kcal·mol−1 each) to binding and are selective if the cysteine position is unique.
4.
There is access to both catalytic and auxiliary interaction sites:
○
By using aromatic and ionic interactions, compound 5c can engage secondary pockets/side-chains that the sugar does not exploit. Those extra contact points increase specificity and the chance of outcompeting natural substrate at realistic concentrations.
5.
There is lower susceptibility to catalytic turnover:
○
Compound 5c appears to be a non-reactive binder (hydrazone/carbohydrazide moieties)—it is unlikely to be converted by the enzyme. This means it can stay bound longer (longer residence time), increasing inhibitory potency even if the equilibrium Kd is modest.
6.
The compound exhibits better cellular activity because of its favorable physicochemical properties.
○
Compared to a phosphate-bearing native ligand, the 5c compound’s pKa, lipophilicity, and overall neutral/partly basic character (piperazine) will usually give better membrane permeability and intracellular concentration.

3.4. Drug Likeness Properties and ADMET Prediction

The drug-likeness characterization of compounds 4b and 5c was evaluated using key physicochemical parameters associated with oral bioavailability, including Lipinski’s RO5 (Table 4), through the SwissADME tool. (http://www.swissadme.ch/index.php) (accessed on 14 September 2025).
According to Lipinski’s rule of five, the studied compounds 4b and 5c could have high chances of oral bioavailability due to their compatibility with Lipinski’s rule of five as follows: the molecular weights (< 500), H-bond donor (HBD ≤ 5), H-bond acceptor (HBA ≤ 10), and atomic molar reactivity (MR) (40 to 130) (Table 4).
The ADMET profile of compounds 4b and 5c was evaluated using the pkCSM website (http://biosig.unimelb.edu.au/pkcsm/) (accessed on 14 September 2025) as presented in Table 5.
The ADMET analysis of compounds 4b and 5c provides a comprehensive overview of their pharmacokinetic and safety profiles, revealing promising yet distinct properties for both molecules (Table 5).
Absorption
Both compounds demonstrated acceptable water solubility, falling within the “soluble” range (log S between −4 and −2). Compound 4b (−2.903) exhibited slightly higher solubility than 5c (−2.962), which may contribute to its superior intestinal absorption (85.03% vs. 70.57%). The Caco-2 permeability of 4b (0.926) also surpasses the threshold for high permeability (log Papp > 0.9), suggesting efficient membrane transport, whereas 5c (0.201) displays moderate permeability. Both compounds are predicted P-glycoprotein substrates and inhibitors (types I and II), indicating the potential for self-inhibition of efflux and improved bioavailability but also possible drug–drug interaction risks.
Distribution
The blood–brain barrier (BBB) permeability values (log BB < −1) suggest that neither compound efficiently penetrates the CNS. However, 4b (−0.97) is marginally closer to the threshold than 5c (−1.25), implying limited but somewhat higher brain exposure. Similarly, CNS permeability (log PS) indicates low central penetration for both, with 4b (−1.69) performing slightly better than 5c (−2.43). These results imply that both molecules are primarily peripherally distributed, which may be beneficial for targeting non-CNS infections or metabolic diseases while reducing neurotoxicity risk.
Metabolism
The metabolic profiles indicate that both compounds interact with multiple cytochrome P450 (CYP) isoenzymes. Compound 4b inhibits several key isoforms, including CYP2D6, CYP3A4, CYP1A2, CYP2C19, and CYP2C9, suggesting a higher likelihood of metabolic interference or drug–drug interactions. Compound 5c exhibits a more selective inhibition pattern (CYP2C9 and CYP3A4 only), implying a cleaner metabolic profile and potentially fewer interaction liabilities.
Excretion
Compound 4b also displayed higher total clearance (0.419 log ml/min/kg) than 5c (0.052), reflecting a faster elimination rate, which may shorten its systemic half-life but reduce accumulation-related toxicity. Both compounds are renal OCT2 substrates, suggesting a renal excretion route through active tubular secretion.
Toxicity
From a toxicity perspective, 4b showed a positive AMES test, indicating potential mutagenicity, whereas 5c was non-mutagenic, which favors its safety profile. However, 5c was predicted to be hepatotoxic, while 4b was not, suggesting that each compound presents distinct toxicity concerns. Both exhibited no hERG I inhibition, minimizing the risk of cardiac arrhythmia, though hERG II inhibition was positive for both, warranting further cardiotoxicity assessment. The LD50 values (2.665 and 2.465 mol/kg for 4b and 5c, respectively) indicate comparable acute toxicity levels, while both compounds were non-sensitizing to the skin.

4. Conclusions

A unique family of either hydrazide–hydrazone derivatives 3, 5, 6, and 7 or imidazolyl pyrazoles 4 was synthesized with high efficiency, starting with 4-methyl-2-phenyl-1H-imidazole-5-carbohydrazide 1. The developed compounds exhibited satisfactory antibacterial efficacy. All the evaluated compounds exhibited antibacterial activity against both Gram-negative and Gram-positive bacteria. Compounds 4b and 5c exhibited the highest efficacy against S. aureus, demonstrating inhibition zones of 2.7 cm and a MIC of 50 µg/mL. Compounds 3a and 3b exhibited modest antifungal action against yeast, whereas compounds 3a, 3b, 5b, 5e, and 5f showed moderate activity against filamentous fungus. These go parallel with the published works on these classes of compounds. The in silico molecular docking study results showed that compounds 4b and 5c have minimum binding energy and have good affinity toward the active pocket; thus, they may be considered as good inhibitors of GlcN-6-P synthase.

Supplementary Materials

The following supporting information can be downloaded at: https://www.mdpi.com/article/10.3390/chemistry7060172/s1, Pages S1–S28 include the IR spectrum and 1H & 13C NMR spectrum of compounds 3a, 3b, 4a, 4b, 5b, 5c, 5d, 5f, 6, and 7.

Funding

This research received no external funding.

Data Availability Statement

The data is available in the Supplementary Materials.

Acknowledgments

The author thanks Sahera F. Mohamed, Department of Physical Sciences, Chemistry Division, College of Science, Jazan University, Jazan, Kingdom of Saudi Arabia, for handling the antimicrobial properties.

Conflicts of Interest

The author declares no conflicts of interest.

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Figure 1. Imidazole-containing drug molecules.
Figure 1. Imidazole-containing drug molecules.
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Figure 2. Hydrazone-containing drug molecules.
Figure 2. Hydrazone-containing drug molecules.
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Scheme 1. Synthesis of hydrazones 3 and imidazolyl pyrazoles 4.
Scheme 1. Synthesis of hydrazones 3 and imidazolyl pyrazoles 4.
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Scheme 2. Synthesis of compounds 5a–f.
Scheme 2. Synthesis of compounds 5a–f.
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Scheme 3. Synthesis of compounds 6 and 7.
Scheme 3. Synthesis of compounds 6 and 7.
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Figure 3. (a,c) represent the 3D orientation of 4b and 5c inside the active pocket of glucosamine-6-phosphate of GlcN-6-P synthase (PDB ID: 2VF5); (b,d) represent the 2D configurations of 4b and 5c inside the active pocket of glucosamine-6-phosphate of GlcN-6-P synthase (PDB ID: 2VF5).
Figure 3. (a,c) represent the 3D orientation of 4b and 5c inside the active pocket of glucosamine-6-phosphate of GlcN-6-P synthase (PDB ID: 2VF5); (b,d) represent the 2D configurations of 4b and 5c inside the active pocket of glucosamine-6-phosphate of GlcN-6-P synthase (PDB ID: 2VF5).
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Table 1. Antimicrobial activities.
Table 1. Antimicrobial activities.
Sample No.Inhibition Zone (cm)
Escherichia coli (ATCC 25922)Pseudomonas aeruginosa (ATCC 25619)Staphylococcus
aureus (ATCC 25923)		Candida
albicans		Rhizopus
racemosus
3a1.5 ± 0.21.4 ± 0.011.3± 0.051.0 ± 0.021.2 ± 0.05
3b1.3 ± 0.021.3 ± 0.021.6 ± 0.021.0 ± 0.021.1 ± 0.02
4a01.0 ± 0.22.4 ± 0.0100
4b2.0 ± 0.052.2 ± 0.022.7 ± 0.0500
5a1.4 ± 0.11.5 ± 0.012.5 ± 0.0100
5b1.7 ± 0.32 ± 0.022.0 ± 0.101.4 ± 0.02
5c1.7 ± 0.031.7 ± 0.012.7 ± 0.0100
5d1.4 ± 0.021.5 ± 0.012.5 ± 0.0200
5e1.6 ± 0.022.0 ± 0.1001.1 ± 0.01
5f1.5 ± 0.11.7 ± 0.022.5 ± 0.0101.2 ± 0.01
61.6 ± 0.022,0 ± 0.021.3 ± 0.0200
71.0 ± 0.021.4 ± 0.011.0 ± 0.0200
Amikacin1.7 ± 0.021.7 ± 0.022.0 ± 0.01--
Neomycin---1.8 ± 0.011.7 ± 0.01
Values are given as the mean ± SD, n = 3.
Table 2. Minimum inhibitory concentration.
Table 2. Minimum inhibitory concentration.
Sample No.MIC (µg/mL)
Escherichia coli (ATCC 25922)Pseudomonas aeruginosa (ATCC 25619)Staphylococcus aureus (ATCC 25923)Candida
albicans		Rhizopus
racemosus
3a200 ± 1.1150 ± 0.02300 ± 0.02300 ± 0.02300 ± 1.0
3b300 ± 0.02200 ± 0.01300 ± 0.1300 ± 0.02300 ± 1.0
4a-300 ± 0.03200 ± 1.0--
4b200 ± 0.05200 ± 1.050 ± 0.01--
5a300 ± 0.02200 ± 0.02100 ± 0.02-300 ± 0.02
5b300 ± 1.o200 ± 0.01100 ± 0.02--
5c200 ± 0.02150 ± 0.0250 ± 0.01--
5d300 ± 0.02200 ± 0.05200 ± 0.02--
5e300 ± 0.03150 ± 0.01--300 ± 0.02
5f300 ± 0.03200 ± 0.05200 ± 0.02-300 ±0.05
6300 ± 0.01200 ± 0.02---
7300 ± 0.02200 ± 0.02---
Values are given as the mean ± SD, n = 3.
Table 3. The molecular docking result of compounds 4b and 5c with the active site of glucosamine-6-phosphate of GlcN-6-P synthase (PDB ID: 2VF5 a bacterial protein of E. coli).
Table 3. The molecular docking result of compounds 4b and 5c with the active site of glucosamine-6-phosphate of GlcN-6-P synthase (PDB ID: 2VF5 a bacterial protein of E. coli).
Comp. No.Score Kcal/molMoieties from
the Compound		Amino Acid ResiduesType of Interaction, Distance Å of H-Bonds
The co-crystallized ligand (GLP)−6.2Phosphate groupTHR352, GLN348, SER303, SER349, CYS300, SER347, LYS603Conventional H-bond
4b−8.7Sugar moiety THR302, VAL399, ALA602, ALA400, GLY301
COTHR302Conventional H-bond
Unfavorable Acceptor—Acceptor
NH of imidazoleGLN348C-H bond
C=CGLU488Pi-Anion
CH3LEU480Alkyl
Phenyl LEU484Alkyl
5c−8.7N-pyrazoleSER401Conventional H-bond
NH-imidazoleALA602
NHLYS603
N-pyrazolGLU488Unfavorable Acceptor—Acceptor
N=N pyrazoleALA400C-H bond
PhenylCYS300Pi-Sulfur
PyrazoleLEU601Pi-Sigma
ClLEU346Halogen
CH3LEU484Alkyl
ClALA299
CYS300
PhenylVAL605
Table 4. Physicochemical characterization of compounds 4b and 5c via the SwissADME online server.
Table 4. Physicochemical characterization of compounds 4b and 5c via the SwissADME online server.
Properties4b5c
Physicochemical Properties
Chemical FormulaC20H17ClN6C26H32N8O
MW (g/mol)376.84472.597
HBA45
HBD23
MR117.81148.31
TPSA (Å2)77.79101.01
No. Lipinski violation0 violation0 violation
Lipinski drug-likeYesYes
MW: Molecular weight ≤ 500; HBA: Hydrogen bond acceptor ≤10; HBD: Hydrogen bond donor ≤5; MR: Molar reactivity (40 ≤ MR ≤ 130), TPSA: Topological polar surface area Å2 TPSA ≤ 140Å2.
Table 5. ADMET study of compounds 4b and 5c using the pkCSM server.
Table 5. ADMET study of compounds 4b and 5c using the pkCSM server.
Parameters * (Unite)4b5c
Absorption
Water solubility (log mol/L)−2.903−2.962
Caco2 permeability (log Papp in 10−6 cm/s)0.9260.201
Intestinal absorption (% Absorbed) 85.0370.567
Skin Permeability (log Kp)−2.735−2.735
P-glycoprotein substrateYesYes
P-glycoprotein I inhibitorYesYes
P-glycoprotein II inhibitorYesYes
Distribution
BBB permeability (log BB)−0.97−1.251
CNS permeability (log PS)−1.69−2.429
Metabolism
CYP2D6 inhibitorYesNo
CYP3A4 inhibitorYesYes
CYP1A2 inhibitorYesNo
CYP2C19 inhibitorYesNo
CYP2C9 inhibitorYesYes
CYP2D6 inhibitorYesYes
CYP3A4 inhibitorYesNo
Excretion
Total Clearance (log ml/min/kg)0.4190.052
Renal OCT2 substrateYesYes
Toxicity
AMES toxicityYesNo
Max. tolerated dose (human) (log mg/kg/day)0.2260.167
hERG I inhibitorNoNo
hERG II inhibitorYesYes
Oral Rat Acute Toxicity (LD50) (mol/kg)2.6652.465
HepatotoxicityNoYes
Skin SensitisationNoNo
* Solubility is classified by log S values: very soluble (>0), extremely soluble (−2 to 0), soluble (−4 to −2), moderately soluble (−6 to −4), weakly soluble (−10 to −6), and insoluble (<−10). High Caco-2 permeability is indicated by log Papp > 0.9; low skin permeability by log Kp > −2.5. Compounds with log BB > 0.3 readily cross the blood–brain barrier, while those with log BB < −1 are poorly distributed to the brain. Central nervous system (CNS) penetration is expected if log PS > −2, but unlikely if log PS < −3.
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Borik, R.M. Design, Synthesis, and Molecular Docking of New Hydrazide–Hydrazone Derivatives with Imidazole Scaffold as Potential Antimicrobial Agents. Chemistry 2025, 7, 172. https://doi.org/10.3390/chemistry7060172

AMA Style

Borik RM. Design, Synthesis, and Molecular Docking of New Hydrazide–Hydrazone Derivatives with Imidazole Scaffold as Potential Antimicrobial Agents. Chemistry. 2025; 7(6):172. https://doi.org/10.3390/chemistry7060172

Chicago/Turabian Style

Borik, Rita M. 2025. "Design, Synthesis, and Molecular Docking of New Hydrazide–Hydrazone Derivatives with Imidazole Scaffold as Potential Antimicrobial Agents" Chemistry 7, no. 6: 172. https://doi.org/10.3390/chemistry7060172

APA Style

Borik, R. M. (2025). Design, Synthesis, and Molecular Docking of New Hydrazide–Hydrazone Derivatives with Imidazole Scaffold as Potential Antimicrobial Agents. Chemistry, 7(6), 172. https://doi.org/10.3390/chemistry7060172

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