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Article

Novel Hydrazide Hydrazone Derivatives as Antimicrobial Agents: Design, Synthesis, and Molecular Dynamics

by
Fatimah Agili
Department of Physical Sciences, Chemistry Division, College of Science, Jazan University, P.O. Box 114, Jazan 45142, Saudi Arabia
Processes 2024, 12(6), 1055; https://doi.org/10.3390/pr12061055
Submission received: 18 April 2024 / Revised: 13 May 2024 / Accepted: 15 May 2024 / Published: 22 May 2024
(This article belongs to the Section Chemical Processes and Systems)
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Abstract

:
Ester 2 was produced by reacting thiourea derivative 1 with ethyl 2-chloro-3-oxobutanoate in MeOH containing piperidine. Hydrazide 3 was produced by reacting the latter ester with hydrazine hydrate in EtOH at reflux. By reacting hydrazide 3 with aromatic/heterocyclic aldehydes, twelve derivatives of hydrazide hydrazone 5a–l were produced. Spectral measurements and elemental analysis verified the molecular structure. Compounds 2, 5a, 5c, 5d, and 5f had strong effects on all the pathogenic bacterial strains according to an evaluation of the antimicrobial qualities of the synthetic compounds. With inhibitory zone diameters ranging from 16 to 20.4 mm, hydrazide hydrazone 5f exhibited the strongest activity. Additionally, the minimum inhibitory concentration (MIC) was assessed. The best outcomes were found with hydrazones 5c and 5f. For B. subtilis, the MIC of 5c was 2.5 mg/mL. For E. coli and K. pneumoniae, the MIC of 5f was 2.5 mg/mL. The molecular mechanics-generalized born surface area (MM/GBSA) was utilized to compute binding free energies via a molecular dynamics simulation analysis of the most active compounds, 5f and 5c. Moreover, computational analyses demonstrated that 5f had a substantial affinity for the active site of DNA gyrase B, suggesting that this compound could be a strong platform for new structure-based design efforts.

1. Introduction

Antimicrobial resistance (AMR) is currently a persistent global public health issue, causing a projected 10 million deaths annually worldwide by 2050. Antimicrobial resistance (AMR) refers to the phenomenon where microorganisms such as viruses, bacteria, fungi, and parasites become resistant to the effects of antimicrobial treatments in both humans and animals. This resistance enables the microorganisms to survive within the host [1,2,3]. This issue has motivated investigations of novel antimicrobial agents derived from either natural or synthetic sources.
The pharmacological activity of hydrazide hydrazone derivatives is attributed to their azomethine group (-NH–N=CH-), which makes them important families in organic chemistry [4,5,6,7,8,9,10]. A wide range of pharmacological characteristics, including antibacterial, antifungal, antitubercular, and antioxidant activities, are known for this family [11,12]. According to a recent publication, 3-hydroxy-2-naphthohydrazide hydrazones have significant antiproliferative effects in human cancer cell lines [13], and 2-hydroxy-4-iodobenzohydrazide hydrazones have potent bactericidal effects on certain cocci and bacilli [14]. It was reported that hydrazide–hydrazones had notable antibacterial effects and, in some cases, much greater activity than reference drugs. They have the potential to affect the strength of the cell wall and cell membrane of microbial cells [15,16,17,18,19]. Certain medications that have hydrazide–hydrazone/hydrazone moieties, such as nitrofurazone, furazolidone, and nitrofurantoin, are depicted in Figure 1.
However, hydrazide–hydrazone derivatives are extremely reactive intermediates because of their acidic NH proton, electrophilic, and nucleophilic sites. Therefore, they can be used as useful intermediaries in the synthesis of different heterocyclic rings [20,21], as well as ligands, to produce metal complexes [22,23,24,25]. Heating the appropriate acid hydrazides with aldehydes or ketones in a variety of organic solvents, such as EtOH, MeOH, BuOH, THF, or AcOH, was the main technique for producing hydrazide-hydrazones. Recently, Borik R. M. [26] conducted a study in our laboratory on the synthesis of chalcones bearing 2-(3-cyano-4,6-dimethyl-2-oxopyridin-1(2H)-yl) amino)-4-methylthiazole as an antibacterial and antioxidant agent. In this study, I describe the synthesis of new hydrazine derivatives derived from 2-((3-cyano-4,6-dimethyl-2-oxopyridin-1(2H)-yl) amino)-4-methylthiazole-5-carbohydrazide 3. These hydrazones have been developed as antimicrobial agents. This research built upon previous work and took into account the advantages associated with these compounds [27,28,29,30,31,32].

2. Results and Discussion

2.1. Chemistry

The synthesis of the new ester 2 and hydrazide 3 is depicted in Scheme 1. Ethyl thiazole-5-carboxylate 2 was produced with excellent yield when thiourea derivative 1 [33] was treated with ethyl 2-chloro-3-oxobutanoate in MeOH with piperidine at reflux. To obtain the corresponding hydrazide 3 with a good yield, ester 2 was treated with hydrazine monohydrate in EtOH at reflux. The spectroscopic data clarified the structures of compounds 2 and 3. The IR spectrum of 2 showed absorption bands at 3408, 2222, 1711, and 1653 cm−1 due to the NH; CN; C=O, ester; and C=O, cyclic amide, respectively. Due to the presence of three Me, a pyridine-H5, and an exchangeable NH group, the 1H NMR spectrum revealed five singlet signals at δ 2.20, 2.36, 2.40, 6.34, and 10.16 ppm. Furthermore, the ethyl group was identified as the source of triplet and quartet signals, which were found at δ 1.21 and 4.17 ppm, respectively. The most significant peaks in the 13C NMR spectrum were at δ 14.2 (Me), 18.6 (Me), 19.2 (Me), 20.7 (Me), 60.6 (CH2), 115.7 (CN), 159.9 (CO, cyclic amide), and 185.6 (CO, ester). The [M+, 30%] ion peak was visible in the mass spectrum at 332. The spectra of hydrazide 3 revealed three bands at 3407–3376, 3334, and 1643 cm−1 (IR); two singlet signals at δ 4.1 and 7.15 ppm (1H NMR); and 162 ppm (13C NMR) due to the hydrazide moiety (CONHNH2).
Hydrazide 3 underwent a condensation reaction with either substituted aromatic aldehydes 4a–f, or heterocycle aldehydes 4g–l, in absolute EtOH with glacial AcOH at reflux for 3–4 h to provide the corresponding hydrazide hydrazones 5a–l in excellent yields (Scheme 2). The structure of hydrazide–hydrazones 5a–l was validated using spectroscopic data. The IR spectrum of 5a, an example of aromatic hydrazone, displayed an absorption band for C=N at 1581 cm−1 and the disappearance of an NH2 band at 3407–3376 cm−1. Its 1H NMR spectrum exhibited three singlets at δ 2.91, and 7.80 ppm for 6H and 1H, respectively, which were generated by NMe2 and azomethine (CH=N) [33], respectively. Additionally, two doublet signals corresponding to aromatic protons were observed at δ 6.67 and 7.51 ppm with J = 8.6 Hz. The 13C NMR spectrum of 5a showed 19 carbon peaks, and the most valuable peaks resonated at δ 40.3, 117, 150.8, 158.7, and 170 ppm because of NMe2, CN, C=N, (C=O cyclic amide), and (C=O hydrazide), respectively. The mass spectrum showed its molecular ion peak at m/z 449, which corresponded to its molecular weight.
Furthermore, the IR spectrum data of 5g, an example of heterocyclic hydrazone, showed absorption bands at 3425, 1659, and 1582 cm−1 due to the hydrazide hydrazone moiety (-CONHN=C-). The 1H NMR spectrum revealed three singlet signals at 8.12, 8.19, and 10.87 ppm owing to the azamethine proton and NH (D2O exchangeable). In addition, triplet and two doublet signals at δ 7.05, 7.30, and 7.52 ppm due to thiophene-H were observed. The 13C NMR spectrum exhibited 18 carbon peaks. The most important peaks resonated at δ 116.9, 153.6, 158.6, and 169.2 ppm due to CN, C=N, and the two carbonyl functions of cyclic amide and hydrazide, respectively.

2.2. Antimicrobial Activity

The effectiveness of the synthesized compounds was assessed by testing them against various bacterial species and yeasts (Table 1). According to these data, compounds 3, 5b, 5e, 5g, 5h, 5i, 5j, 5k, and 5l did not exhibit any inhibitory action against the microorganisms under examination. Furthermore, compound 5e was effective against only one strain of S. aureus, with a moderate inhibition zone width (5.1 ± 0.17). Furthermore, against each compound, the yeast strain (C. albicans) exhibited no inhibitory action. Compounds 2, 5a, 5c, 5d, and 5f, on the other hand, had varying inhibition zones (6.1–20.4 mm) against all pathogenic bacterial strains. The activities were as follows: 5f > 5c > 5d > 2 > 5a. Compound 5f had the maximum activity, with inhibition zone diameters measuring 20.4 ± 0.25 mm for B. subtilis, 16.9 ± 0.29 mm for E. coli, 16.0 ± 0.31 mm for S. aureus, and 19.9 ± 0.71 mm for K. pneumoniae. However, tests were also carried out to determine the minimum inhibitory concentration (MIC) of the most potent substances against pathogenic bacteria (Table 2). The compounds with the best outcomes were 5c and 5f. B. subtilis ATCC 6051 was the target of 2.5 mg/mL of 5c. Regarding E. coli ATCC 25922 and K. pneumoniae ATCC 13883, the MIC for 5f was 2.5 mg/mL.
In terms of structural activity relationships, the antibacterial action of the synthesized compounds could be attributed to the presence of imino (-CH=N-), amino (NH2), and cyano (CN) groups. Moreover, the presence of a thiazol ring could enhance their antibacterial characteristics. Furthermore, compounds 5f, 5c, and 5d, which contained hydroxyl, bromo, and methoxy groups, respectively, showed potent activity. Hydrazides and hydrazones have the potential to affect the strength of the cell wall and cell membrane of microbial cells [34].

2.3. Molecular Dynamic and System Stability

In this work, the stability of the systems was evaluated during 20 ns simulations using the root mean square deviation (RMSD). The average recorded RMSD values for the full frames of the systems were 1.41 ± 0.23 Å, 1.27 ± 0.25 Å, and 1.03 ± 0.13 Å for the apo-, 5f- and 5c-complex systems, respectively (Figure 2A).
To understand the behavior of residues and how they relate to the ligand, an evaluation of the elasticity of enzymes after binding to the ligand in MD simulation is required [35]. Using the root mean square fluctuation (RMSF) approach, protein residue variations were assessed over a set of 20 ns simulations. For the systems with the apo-, 5f-, and 5c-complex systems, the mean RMSF values for all frames were 1.05 ± 0.47 Å, 0.97 ± 0.51 Å, and 0.94 ± 0.53 Å, respectively. The findings showed that, compared to the other two systems, the complicated structure of 5f bound to protein had less variation in residues (Figure 2B).
The stability of the amino acid structures during the simulation is indicated by the radius of gyration, Rg. The mean reported ROG values for the complex systems apo, 5f, and 5c were 16.72 ± 0.06 Å, 16.64 ± 0.08 Å, and 16.63 ± 0.06 Å, respectively (Figure 2C). The Rg structure of the 5f-bonded proteins was less rigid than that of the apo protein.
The solvent-accessible surface area (SASA) of the hydrophobic core of the protein was evaluated to estimate its compactness. To do this, the solvent-visible surface area of the protein was evaluated, which was significant for biomolecule stability [36] Figure 2D shows that the average SASA values for the entire frames of the apo-, 5f- and 5c-complex systems were 9824.60 Å, 9533.15 Å, and 9308.30 Å, respectively.

2.3.1. The Binding Interaction Mechanism

Binding free energies were calculated using snapshots from the system trajectories and the AMBER18 MM-GBSA tool (version number 18) [37]. Except for ΔGsolv, Table 3 demonstrates that all reported computed energy components had significantly negative values, indicating positive interactions. Compounds 5c and 5f had binding affinities of −29.87 kcal/mol and −32.99 kcal/mol, respectively, to the DNA gyrase protein. The highest positive van der Waals energy and the electrostatic component, respectively, were responsible for the contacts between 5f/5c and the DNA gyrase receptor residues (Table 3).

2.3.2. Finding the Essential Residues in Charge of Ligand Binding

In Figure 3, the main favorable contribution of the 5c compound to the DNA gyrase protein receptor was predominantly observed from residues Glu25 (−0.223 kcal/mol), Ile26 (−0.121 kcal/mol), Asn29 (−0.154 kcal/mol), Ser30 (−0.596 kcal/mol), Glu33 (−0.343 kcal/mol), Asp56 (−0.293 kcal/mol), Gly58 (−0.391 kcal/mol), Arg 59 (−1.299 kcal/mol), Gly60 (−0.488 kcal/mol), Ile61 (−3.322 kcal/mol), Pro62 (−2.09 kcal/mol), Gln66 (−0.856 kcal/mol), Lys68 (−0.627 kcal/mol), Met69 (−0.694 kcal/mol), Ala73 (−0.481 kcal/mol), Val74 (−0.629 kcal/mol), Glu75 (−0.216 kcal/mol), Val 76 (−0.984 kcal/mol), and Ile 77 (−2.077 kcal/mol).
For compound 5f to the DNA gyrase protein receptor, it was observed from residues Gln41 (−2.225 kcal/mol), Ile42 (−0.407 kcal/mol), Glu43 (−1.106 kcal/mol), Thr55 (−0.717 kcal/mol), Asp56 (−0.277 kcal/mol), Asn57 (−1.141 kcal/mol), Gly58 (−0.163 kcal/mol), Hie99 (−0.195 kcal/mol), Lys126 (−1.409 kcal/mol), Thr 127 (−0.92 kcal/mol), Gly128 (−0.15 kcal/mol), Ile167 (−0.14 kcal/mol), Thr168 (−1.995 kcal/mol), Ser182 (−0.331 kcal/mol), and Tyr183 (−0.037 kcal/mol).

2.3.3. Patterns of Ligand–Residue Interactions in Networks

DNA synthesis stops and eventually leads to cell death when DNA gyrase, an enzyme essential for bacteria, is inhibited. Therefore, it has long been known that DNA gyrase represents a potential target for antibacterial drugs [38]. The structural connections between 5c and 5f in the catalytic binding region of the DNA gyrase receptor were found to be hydrophobic and electrostatic.
Compound 5c, which is suitable in the catalytic active area of DNA gyrase B, was confirmed to generate a stable hydrogen bond contact with Gly 60 (Figure 4). In addition, the p-bromo phenyl ring showed pi-alkyl interaction with Met 69. Furthermore, a pi-alkyl connection was created between Iles 61, 77, and 131 and the tetrahydropyridine ring. The thiazole ring was also found to create pi-alkyl interactions with Pro 62 and Ile 77. Additionally, the thiazole and pyridone ring joined forces to form a Pi-alkyl bond with the pharmacophoric hotspot, residue Ile 61. A Pi–anion connection was finally created through Glu 33 and the tetrahydropyridine ring.
On the other hand, 5f interacted with the residues of the active sites of ATPase through the formation of a hydrogen bond interaction with the residue Ile 42. The Lys 126 pharmacophoric hotspot residue generated Pi-sigma, Pi-alkyl, and hydrogen bonding interactions with dihydroxyphenyl and thiazole rings. Finally, a Pi–anion link was established between Glu 43 and the pyridone ring (Figure 4).

3. Experimental Section

3.1. Chemistry

General: Melting points were not corrected and were 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). Data were analyzed with an MS-50 Kratos (A.E.I.) spectrometer, which was used to obtain mass spectra at 70 eV. Using CDCl3 or DMSO-d6 as an internal standard and TMS 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). 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.
Ethyl 2-((3-cyano-4,6-dimethyl-2-oxopyridin-1(2H)-yl)amino)-4-methylthiazole-5-carboxylate (2). In MeOH (20 mL), which contains a catalytic amount of piperidine, a mixture of thiourea derivative 1 (5 mmol, 1.11 g) and ethyl 2-chloro-3-oxobutanoate (5 mmol, 0.82 g) was heated at reflux for 8 h. The white precipitate that had formed after cooling was filtered off, washed with ethanol, and dried under reduced pressure. White crystals, yield (90%), mp. 264–265 °C. IR (KBr, υmax, cm−1): 3408 (NH), 2222 (CN), 1711 (CO, ester), 1653 (CO, amide); 1HNMR (500 MHz, DMSO-d6): δ 1.21 (t, 3H, CH3), 2.20 (s, 3H, CH3), 2.36 (s, 3H, CH3), 2.40 (s, 3H, CH3), 4.17 (q, 2H, CH2), 6.34 (s, 1H, Py-H5), 10.16 (s, 1H, NH, D2O exchangeable) ppm; 13C NMR (DMSO-d6) δc (ppm): 14.2 (Me), 18.6 (Me), 19.2 (Me), 20.7 (Me), 60.6 (CH2), 101, 108.6, 115.7 (CN), 153.8, 155.6, 158.7, 159.9 (CO, cyclic amide), 169, 181.5, 185.6 (CO, ester); EI-MS 332 [M+, 30%], 148 (100%); anal. calcd. for: C15H16N4O3S: C, 54.20; H, 4.85; N, 16.86; found: C, 53.92; H, 4.57; N, 16.61.
2-((3-Cyano-4,6-dimethyl-2-oxopyridin-1(2H)-yl)amino)-4-methylthiazole-5-carbohydrazide (3). Ester 2 (5 mmol, 1.66 g) and hydrazine hydrate (8 mmol, 0.4 g) were mixed in EtOH (20 mL) and heated for 4 h at reflux. After being cooled, the resulting white precipitate was filtered off, washed with ethanol, and dried under low pressure. White solid, yield (85%), mp. 245–246 °C. IR (KBr, υmax, cm−1): 3407–3376 (NH2), 3334 (NH), 3236 (NH), 2217 (CN), 1643 (CO, hydrazide), 1611 (CO, cyclic amide); 1HNMR (500 MHz, DMSO-d6): δ 2.17 (s, 3H, CH3), 2.26 (s, 3H, CH3), 2.31 (s, 3H, CH3), 4.1 (s, 2H, NH2), 5.8 (s, 1H, NH, D2O exchangeable), 6.20 (s, 1H, Py-H5), 7.15 (s, 1H, NH, D2O exchangeable) ppm; 13C NMR (DMSO-d6) δc (ppm): 18.3 (Me), 19.9 (Me), 20.7 (Me), 99.1, 102.2, 108, 117.7 (CN), 143.4, 144.1, 145.5, 154.3, 159.4 (CO, cyclic amide), 162 (CO, hydrazide); EI-MS 318 [M+, 20%], 148 (100%); anal. calcd. for: C13H14N6O2S: C, 49.05; H, 4.43; N, 26.40; found: C, 48.83; H, 4.26; N, 26.22.
General procedure for the synthesis of hydrazide hydrazone derivatives 5a–l.
A mixture of hydrazide 3 (1 mmol, 0.318 g) and aromatic aldehydes 4a–l (1 mmol) were heated in EtOH (25 mL) with a catalytic amount of glacial AcOH at reflux for 3–4 h (TLC). Hydrazide hydrazone derivatives 5a–l were obtained by filtering out the precipitate, drying it under low pressure, and then recrystallizing it from EtOH.
2-((3-Cyano-4,6-dimethyl-2-oxopyridin-1(2H)-yl)amino)-N′-(4-(dimethylamino)benzylidene)-4-methylthiazole-5-carbohydrazide (5a). Color: white solid; mp. 255–256 °C. IR (KBr, υmax, cm−1): 3465 (NH), 3175 (NH), 2214 (CN), 1657 (CO, hydrazide), 1637 (CO, cyclic amide), 1581 (C=N); 1HNMR (500 MHz, DMSO-d6): δ 2.20 (s, 3H, CH3), 2.27 (s, 3H, CH3), 2.47 (s, 3H, CH3), 2.91 (s, 6H, NMe2), 6.23 (s, 1H, py-H5), 6.67 (d, 2H, J = 8.6 Hz, Ar-H), 7.51 (d, 2H, J = 8.6 Hz, Ar-H), 7.80&7.88 (s, 1H, CH=N), 9.6 (s, H, NH, D2O exchangeable), 10.6 (s, H, NH, D2O exchangeable) ppm; 13C NMR (DMSO-d6) δc (ppm): 17.1 (Me), 19.4 (Me), 20.2 (Me), 40.3 (NMe2), 98.8, 107.7, 111.8, 117 (CN), 122.5, 127.7, 128, 140, 150.8 (C=N), 153.6, 154.6, 157.5, 158.7 (CO, cyclic amide), 165, 170 (CO, hydrazide); EI-MS 449 [M+, 13%], 246 (23%), 148 (100%); anal. calcd. for: C22H23N7O2S: C, 58.78; H, 5.16; N, 21.81; found: C, 58.52; H, 4.93; N, 21.65.
2-((3-Cyano-4,6-dimethyl-2-oxopyridin-1(2H)-yl)amino)-N′-(4-fluorobenzylidene)-4-methylthiazole-5-carbohydrazide (5b). Color: yellow crystals; mp. 205–206 °C. IR (KBr, υmax, cm−1): 3483 (NH), 3177 (NH), 2212 (CN), 1660 (CO, hydrazide), 1641 (CO, cyclic amide), 1577 (C=N); 1HNMR (500 MHz, DMSO-d6): δ 2.20 (s, 3H, CH3), 2.27 (s, 3H, CH3), 2.29 (s, 3H, CH3), 6.26 (s, 1H, Py-H5), 7.20 (t, 2H, J = 8.6, Ar-H), 7.34 (d, 2H, J = 9 Hz, Ar-H), 8.68 & 8.70 (s, 1H, CH=N), 10 (s, H, NH, D2O exchangeable), 10.90 (s, H, NH, D2O exchangeable) ppm; 13C NMR (DMSO-d6) δc (ppm): 18.6 (Me), 19.3 (Me), 20.2 (Me), 99, 107.7, 115.9 (CN), 128.7, 130.7, 131.5, 139, 153.5 (C=N), 154.9, 157.5, 158.6 (CO, cyclic amide), 160.4, 164.1, 165.6, 167.3 (CO, hydrazide); EI-MS 424 [M+, 22%], 406 (5%), 246 (20%), 148 (100%); anal. calcd. for: C20H17FN6O2S: C, 56.60; H, 4.04; N, 19.80; found: C, 56.39; H, 3.87; N, 19.65.
N′-(4-Bromobenzylidene)-2-((3-cyano-4,6-dimethyl-2-oxopyridin-1(2H)-yl)amino)-4-methylthiazole-5-carbohydrazide (5c). Color: white powder; mp. 210–211 °C. IR (KBr, υmax, cm−1): 3461 (NH), 3175 (NH), 2216 (CN), 1657 (CO, hydrazide), 1640 (CO, cyclic amide), 1580 (C=N); 1HNMR (500 MHz, DMSO-d6): δ 2.21 (s, 3H, CH3), 2.27 (s, 3H, CH3), 2.30 (s, 3H, CH3), 6.30 (s, 1H, Py-H5), 7.25 (d, 2H, J = 8.6 Hz, Ar-H), 7.85 (d, 2H, J = 8.6 Hz, Ar-H), 8.70 & 8.81 (s, 1H, CH=N), 10.21 (s, H, NH, D2O exchangeable), 10.95 (s, H, NH, D2O exchangeable) ppm; 13C NMR (DMSO-d6) δc (ppm): 18.5 (Me), 19.2 (Me), 20.5 (Me), 99, 107.7, 116 (CN), 128.7, 130.5, 131.5, 139, 153.5 (C=N), 155, 157.5, 159.5 (CO, cyclic amide), 161, 164, 165.6, 168 (CO, hydrazide); EI-MS 484 [M+, 13%], 486 [M+ +2, 12%], 246 (25%), 148 (100%); anal. calcd. for: C20H17BrN6O2S: C, 49.49; H, 3.53; N, 17.32; found: C, 49.22; H, 3.34; N, 17.17.
2-((3-Cyano-4,6-dimethyl-2-oxopyridin-1(2H)-yl)amino)-N′-(3,4-dimethoxybenzylidene)-4-methylthiazole-5-carbohydrazide (5d). Color: pale yellow crystals; mp. 210 °C. IR (KBr, υmax, cm−1): 3361 (NH), 3187 (NH), 2214 (CN), 1655 (CO, hydrazide), 1640 (CO, cyclic amide), 1577 (C=N); 1HNMR (500 MHz, DMSO-d6): δ 2.21 (s, 3H, CH3), 2.27 (s, 3H, CH3), 2.47 (s, 3H, CH3), 3.75 (s, 3H, OMe), 3.78 (s, 3H, OMe), 6.25 (s, 1H, Py-H5), 6.91 (d, 1H, J = 5 Hz, Ar-H), 7.10 (d, 1H, J = 10 Hz, Ar-H), 7.42 (s, 1H, Ar-H), 7.85 (s, 1H, CH=N), 9.75 (s, H, NH, D2O exchangeable), 10.73 (s, H, NH, D2O exchangeable) ppm; 13C NMR (DMSO-d6) δc (ppm): 18.6 (Me), 19.4 (Me), 20.3 (Me), 55.6 (OMe), 56 (OMe), 98.8, 107.8, 108.5, 111.3, 117 (CN), 120.9, 127.7, 128.7, 140, 149, 150 (C=N), 153.7, 154.8, 157.4, 158.7 (CO, cyclic amide), 164.1, 168.3 (CO, hydrazide); EI-MS 466 [M+, 7%], 405 (3%), 220 (100%), 148 (63%); anal. calcd. for: C22H22N6O4S: C, 56.64; H, 4.75; N, 18.01; found: C, 56.51; H, 4.58; N, 17.86.
2-((3-Cyano-4,6-dimethyl-2-oxopyridin-1(2H)-yl)amino)-4-methyl-N′-(4-nitrobenzylidene)thiazole-5-carbohydrazide (5e). Color: yellow powder; mp. 265–266 °C. IR (KBr, υmax, cm−1): 3455 (NH), 3180 (NH), 2216 (CN), 1658 (CO, hydrazide), 1641 (CO, cyclic amide), 1582 (C=N); 1HNMR (500 MHz, DMSO-d6): δ 2.23 (s, 3H, CH3), 2.29 (s, 3H, CH3), 2.34 (s, 3H, CH3), 6.31 (s, 1H, Py-H5), 7.30 (d, 2H, J = 8.5 Hz, Ar-H), 7.82 (d, 2H, J = 8.5 Hz, Ar-H), 8.76 & 8.89 (s, 1H, CH=N), 10.18 (s, H, NH, D2O exchangeable), 11 (s, H, NH, D2O exchangeable) ppm; 13C NMR (DMSO-d6) δc (ppm): 18.3 (Me), 19 (Me), 20 (Me), 100, 109, 117 (CN), 129, 130.7, 132, 139.5, 154 (C=N), 155.6, 157.8, 159.5 (CO, cyclic amide), 162, 164, 165.8, 167 (CO, hydrazide); EI-MS 451 [M+, 7%], 246 (23%), 148 (100%); anal. calcd. for: C20H17N7O4S: C, 53.21; H, 3.80; N, 21.72; found: C, 52.97; H, 3.66; N, 21.49.
2-((3-Cyano-4,6-dimethyl-2-oxopyridin-1(2H)-yl)amino)-N′-(2,4-dihydroxybenzylidene)-4-methylthiazole-5-carbohydrazide (5f). Color: white powder; mp. > 300 °C. IR (KBr, υmax, cm−1): 3457 (NH), 3350 (OH), 3170 (NH), 2215 (CN), 1656 (CO, hydrazide), 1640 (CO, cyclic amide), 1586 (C=N); 1HNMR (500 MHz, DMSO-d6): δ 2.23 (s, 3H, CH3), 2.28 (s, 3H, CH3), 2.31 (s, 3H, CH3), 6.23 (s, 1H, Py-H5), 6.42 (s, 1H, Ar-H), 6.88 (m, 2H, Ar-H), 8.68 & 8.80 (s, 1H, CH=N), 10.18 (s, 1H, NH, D2O exchangeable), 10.38 (s, 1H, OH, D2O exchangeable), 10.66 (s, 1H, OH, D2O exchangeable), 11 (s, 1H, NH, D2O exchangeable) ppm; 13C NMR (DMSO-d6) δc (ppm): 17.8 (Me), 18.9 (Me), 20 (Me), 102, 108, 111, 115, 117 (CN), 131.7, 133, 145.5, 155 (C=N), 155.6, 159.5 (CO, cyclic amide), 162, 163.6, 165.8, 168 (CO, hydrazide); EI-MS 438 [M+, 8%], 246 (35%), 148 (100%); anal. calcd. for: C20H18N6O4S: C, 54.79; H, 4.14; N, 19.17; found: C, 54.63; H, 4.03; N, 19.02.
2-((3-Cyano-4,6-dimethyl-2-oxopyridin-1(2H)-yl)amino)-4-methyl-N′-(thiophen-2-ylmethylene)thiazole-5-carbohydrazide (5g). Color: brown crystals; mp. 250–251 °C. IR (KBr, υmax, cm−1): 3452 (NH), 3185 (NH), 2216 (CN), 1659 (CO, hydrazide), 1622 (CO, cyclic amide), 1582 (C=N); 1HNMR (500 MHz, DMSO-d6): δ 2.20 (s, 3H, CH3), 2.27 (s, 3H, CH3), 2.47 (s, 3H, CH3), 6.29 (s, 1H, Py-H5), 7.05 (t, 1H, thiophene-H), 7.30 (d, 1H, J = 3 Hz, thiophene-H), 7.52 (d, 1H, J = 5 Hz, thiophene-H), 8.12 & 8.19 (s, 1H, CH=N), 9.94 (s, H, NH, D2O exchangeable), 10.87 (s, H, NH, D2O exchangeable) ppm; 13C NMR (DMSO-d6) δc (ppm): 17.8 (Me), 19.4 (Me), 20.3 (Me), 98.9, 107.8, 116.9 (CN), 127.4, 127.7, 128.7, 136.3, 139.5, 144, 153.6 (C=N), 155, 157.1, 158.6 (CO, cyclic amide), 163.1, 169.2 (CO, hydrazide); EI-MS 412 [M+, 9%], 246 (43%), 148 (100%); anal. calcd. for: C18H16N6O2S2: C, 52.41; H, 3.91; N, 20.37; found: C, 52.23; H, 3.78; N, 20.19.
2-((3-Cyano-4,6-dimethyl-2-oxopyridin-1(2H)-yl)amino)-N′-(furan-2-ylmethylene)-4-methylthiazole-5-carbohydrazide (5h). Color: white powder; mp. 270–271 °C. IR (KBr, υmax, cm−1): 3457 (NH), 3187 (NH), 2215 (CN), 1662 (CO, hydrazide), 1625 (CO, cyclic amide), 1581 (C=N); 1HNMR (500 MHz, DMSO-d6): δ 2.21 (s, 3H, CH3), 2.26 (s, 3H, CH3), 2.39 (s, 3H, CH3), 6.30 (s, 1H, Py-H5), 6.44 (dd, 1H, J = 1.8 Hz, 3.4 Hz, furan-H), 7 (d, 1H, J = 3.4 Hz, furan-H), 7.50 (d, 1H, J = 3.4 Hz, furan-H), 8.10, 8.25 (s, 1H, CH=N), 9.80 (s, H, NH, D2O exchangeable), 10.70 (s, H, NH, D2O exchangeable) ppm; 13C NMR (DMSO-d6) δc (ppm): 18 (Me), 19.5 (Me), 21 (Me), 101, 108, 117 (CN), 127, 128, 129, 136.3, 139.5, 144, 153.6 (C=N), 155, 157.1, 159.5 (CO, cyclic amide), 163, 167 (CO, hydrazide); EI-MS 396 [M+, 20%], 246 (45%), 148 (100%); anal. calcd. for: C18H16N6O3S: C, 54.54; H, 4.07; N, 21.20; found: C, 54.41; H, 3.93; N, 21.10.
2-((3-Cyano-4,6-dimethyl-2-oxopyridin-1(2H)-yl)amino)-4-methyl-N′-(pyridin-3-ylmethylene)thiazole-5-carbohydrazide (5i). Color: pale yellow powder; mp. 280–281 °C. IR (KBr, υmax, cm−1): 3443 (NH), 3180 (NH), 2222 (CN), 1660 (CO, hydrazide), 1631 (CO, cyclic amide), 1583 (C=N); 1HNMR (500 MHz, DMSO-d6): δ 2.22 (s, 3H, CH3), 2.25 (s, 3H, CH3), 2.35 (s, 3H, CH3), 6.27 (s, 1H, Py-H5), 7.34 (dd, 1H, J = 6 Hz, 7.6 Hz, pyridine-H), 8.20 (d, 1H, J = 7.6 Hz, pyridine-H), 8.12 & 8.30 (s, 1H, CH=N), 8.75 (d, 1H, J = 6 Hz, pyridine-H), 8.95 (s, 1H, pyridine-H), 9.60 (s, H, NH, D2O exchangeable), 10.50 (s, H, NH, D2O exchangeable) ppm; 13C NMR (DMSO-d6) δc (ppm): 17.8 (Me), 18.5 (Me), 20.5 (Me), 108, 115.3, 117 (CN), 127, 130, 121.5, 133.3, 134, 145, 149, 152, 153.6 (C=N), 157.1, 159.5 (CO, cyclic amide), 165, 170 (CO, hydrazide); EI-MS 407 [M+, 10%], 246 (50%), 148 (80%), 118 (100%); anal. calcd. for: C19H17N7O2S: C, 56.01; H, 4.21; N, 24.06; found: C, 55.95; H, 4.05; N, 23.89.
N′-((1H-indol-3-yl)methylene)-2-((3-cyano-4,6-dimethyl-2-oxopyridin-1(2H)-yl)amino)-4-methylthiazole-5-carbohydrazide (5j). Color: white solid; mp. 290–291 °C. IR (KBr, υmax, cm−1): 3464 (NH), 3306 (NH), 3206 (NH), 2220 (CN), 1639 (CO, hydrazide), 1620 (CO, cyclic amide), 1570 (C=N); 1HNMR (500 MHz, DMSO-d6): δ 2.23 (s, 3H, CH3), 2.28 (s, 3H, CH3), 2.47 (s, 3H, CH3), 6.24 (s, 1H, Py-H5), 7.09 (d, 1H, J = 10 Hz, indole-H), 7.15 (d, 1H, J = 5 Hz, indole-H), 7.39 (d, 1H, J = 5 Hz, indole-H), 7.69 (s, 1H, indole-H2), 8.13 (d, 1H, J = 8 Hz, indole-H), 8.18 & 8.24 (s, 1H, CH=N), 9.60 (s, H, NH, D2O exchangeable), 10.53 (s, H, NH, D2O exchangeable), 11.44 (s, H, NH, D2O exchangeable, indole-H) ppm; 13C NMR (DMSO-d6) δc (ppm): 18 (Me), 19.6 (Me), 20.4 (Me), 99, 108.1, 112, 117.2 (CN), 120.5, 121.9, 122.7, 124.2, 129.2, 137.2, 139.2, 144.8, 147, 154 (C=N), 155, 157.6, 159.2 (CO, cyclic amide), 165, 167 (CO, hydrazide); EI-MS 445 [M+, 3%], 244 (30%), 148 (45%), 118 (100%); anal. calcd. for: C22H19N7O2S: C, 59.31; H, 4.30; N, 22.01; found: C, 59.17; H, 4.15; N, 21.85.
N′-((2-Chloroquinolin-3-yl)methylene)-2-((3-cyano-4,6-dimethyl-2-oxopyridin-1(2H)-yl)amino)-4-methylthiazole-5-carbohydrazide (5k). Color: yellow solid; mp. > 300 °C. IR (KBr, υmax, cm−1): 3354 (NH), 3185 (NH), 2218 (CN), 1647 (CO, hydrazide), 1620 (CO, cyclic amide), 1582 (C=N); 1HNMR (500 MHz, DMSO-d6): δ 2.22 (s, 3H, CH3), 2.28 (s, 3H, CH3), 2.47 (s, 3H, CH3), 6.26 (s, 1H, Py-H5), 6.60–7.98 (m, 4H, quinoline-H), 8.35 (s, 1H, quinoline-H4), 8.61 (s, 1H, CH=N), 9.19 (s, H, NH, D2O exchangeable), 11.95 (s, H, NH, D2O exchangeable) ppm; 13C NMR (DMSO-d6) δc (ppm): 17.4 (Me), 18.7 (Me), 20.4 (Me), 105, 114, 117 (CN), 124.3, 126, 127, 128, 128.7, 130.2, 131, 132.4, 136.6, 139, 150, 151.5, 153 (C=N), 155, 159.3 (CO, cyclic amide), 164, 168 (CO, hydrazide); EI-MS 492 [M+, 5%], 314 (10%), 169 (100%); anal. calcd. for: C23H18ClN7O2S: C, 56.15; H, 3.69; N, 19.93; found: C, 55.96; H, 3.53; N, 19.80.
N′-((2-Chloro-6-methylquinolin-3-yl)methylene)-2-((3-cyano-4,6-dimethyl-2-oxopyridin-1(2H)-yl)amino)-4-methylthiazole-5-carbohydrazide (5l). Color: yellow solid; mp. > 300 °C. IR (KBr, υmax, cm−1): 3344 (NH), 3188 (NH), 2220 (CN), 1649 (CO, hydrazide), 1625 (CO, cyclic amide), 1580 (C=N); 1HNMR (500 MHz, DMSO-d6): δ 2.22 (s, 3H, CH3), 2.28 (s, 3H, CH3), 2.43 (s, 3H, CH3), 2.47 (s, 3H, CH3), 6.25 (s, 1H, Py-H5), 6.90–7.91 (m, 3H, quinoline-H), 8.37 (s, 1H, quinoline-H4), 8.56 (s, 1H, CH=N), 9.30 (s, H, NH, D2O exchangeable), 11.40 (s, H, NH, D2O exchangeable) ppm; 13C NMR (DMSO-d6) δc (ppm): 17.4 (Me), 18.7 (Me), 19.5 (Me), 20.4 (Me), 103, 113, 116.5 (CN), 124.6, 125.9, 127, 128, 129.3, 130, 131, 133.2, 135.4, 138.8, 149, 152, 153 (C=N), 155, 159.6 (CO, cyclic amide), 163.5, 167.6 (CO, hydrazide); EI-MS 506 [M+, 10%], 314 (30%), 170 (100%); anal. calcd. for: C24H20ClN7O2S: C, 56.97; H, 3.98; N, 19.38; found: C, 56.70; H, 3.81; N, 19.22.

3.2. Antimicrobial Activity

The agar disc diffusion assay method [39,40] was utilized to ascertain the antimicrobial activity. Bacteria were subcultured in Trypticase soya agar medium (Oxoid Laboratories, Oxoid, UK) and fungi in Sabouraud dextrose agar (Oxoid Laboratories, UK). The positive control in this experiment was gentamycin, whereas the negative control was DMSO solvent. The average zone of inhibition was computed in triplicate when the plates were completed. The other fungal cultures were incubated at 25–30 °C for 3–5 days; the bacterial cultures were incubated at 37 °C for 24 h. The length of inhibition measurement in millimeters (mm) was used to determine the antimicrobial activity.
Sabouraud dextrose agar: The following composition (g/L) of the media was used to isolate the pathogenic yeasts: the pH was adjusted to 5.4 using 20 glucose, 10 peptone, 25 agar, and 1 L of distilled water. After 15 min, the medium was autoclaved at 121 °C. Trypticase soy agar (TSA): The microorganisms under test were grown on this medium. Sodium chloride (5.0 g), agar (15.0 g), soytone (5.0 g), pancreatic digest of casein (15.0 g), and distilled water (1 L) were used. After 15 min, the media were autoclaved at 121 °C.
Cultures of one fungal strain, C. albicans (ATCC 10231), and four bacterial species were utilized, including Gram-positive S. aureus (ATCC 29213) and B. subtilus (ATCC 6051) and Gram-negative K. pneumoniae (ATCC 13883) and E. coli (ATCC 25922). The in vitro antimicrobial screening of the prepared compounds was performed. The antibacterial agent gentamycin was used as a positive control to evaluate the potency of the investigated compounds under the same conditions.

Minimum Inhibitory Concentration (MIC)

Using a two-fold dilution approach [41], the minimum inhibitory concentrations (MICs) of the most active hydrazones against pathogenic bacteria were determined. DMSO was used to dissolve the compounds in accordance with their individual known weights. To perform the disc diffusion method on nutrient agar media, the mother solutions were serially diluted with DMSO and applied to the disc at final concentrations of 2.5, 5.0, and 10.0 mg/mL. The MIC is given in millimeters (mm) and refers to the concentration at which no discernible growth was observed.

3.3. Molecular Dynamic and System Stability

3.3.1. System Preparation

The crystal structure of DNA gyrase B was found using 4URO code [42] to search the protein data database. These structures were then prepared for use with the UCSF Chimera [43] in molecular dynamics (MD) studies. The pH was adjusted to 7.5 using PROPKA (http://propka.ki.ku.dk/) [44]. We sketched two structures with ChemBioDraw Ultra 12.1 [45]. The twenty-nanosecond MD simulations that were run on each of the three prepared systems are detailed in the Simulation Section 3.3.2.

3.3.2. Molecular Dynamics (MD) Simulations

MD simulations were performed for each system using the GPU version of the PMEMD engine from the AMBER 18 package [46]. The calculation of the molecular dynamic method was performed according to the literature [47].

3.3.3. Thermodynamic Calculation

Poisson–Boltzmann, generalized Born, and surface area continuum solvation approaches (MM/PBSA and MM/GBSA) have been demonstrated to be effective relationships for the estimation of ligand binding affinities [48,49,50].

4. Conclusions

A unique family of hydrazide hydrazones 5a-I was synthesized with high efficiency, starting with 2-((3-cyano-4,6-dimethyl-2-oxopyridin-1(2H)-yl)amino)-4-methylthiazole-5-carbohydrazide 3, which was prepared from the corresponding ester 2. The developed compounds exhibited satisfactory antibacterial efficacy. Hydrazones 5c and 5f exhibited notable antibacterial effects, as evidenced by their minimum inhibitory concentration (MIC) value of 2.5 mg/mL. The inclusion of bromo and hydroxyl groups enhanced antibacterial efficacy. Furthermore, the computational analyses showed that 5f exhibited significant affinity for the active region of DNA gyrase B.

Funding

This research received no external funding.

Data Availability Statement

The data used to support the findings of this study are available from the corresponding author upon request.

Acknowledgments

The author thanks Yasser Mokhtar Abd Elmonem, VACSERA, 51 Wezaret Elzeraa Street, Agouza, Giza, Egypt, for handling the antimicrobial properties.

Conflicts of Interest

The author declares no conflicts of interest.

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Figure 1. Some drugs containing hydrazone or hydrazide–hydrazone moieties.
Figure 1. Some drugs containing hydrazone or hydrazide–hydrazone moieties.
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Scheme 1. Synthesis of ester 2 and hydrazide 3.
Scheme 1. Synthesis of ester 2 and hydrazide 3.
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Scheme 2. Synthesis of hydrazide-hydrazones 5a–l.
Scheme 2. Synthesis of hydrazide-hydrazones 5a–l.
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Figure 2. (A) RMSD of Cα atoms of the protein backbone atoms. (B) RMSF of each residue of the protein backbone Cα atoms of protein residues. (C) ROG of Cα atoms of protein residues. (D) Solvent-accessible surface area (SASA) of the Cα of the backbone relative (black) to the starting minimized over 20 ns for the ATP binding site of the DNA gyrase receptor with 5c (red) and 5f ligands (blue).
Figure 2. (A) RMSD of Cα atoms of the protein backbone atoms. (B) RMSF of each residue of the protein backbone Cα atoms of protein residues. (C) ROG of Cα atoms of protein residues. (D) Solvent-accessible surface area (SASA) of the Cα of the backbone relative (black) to the starting minimized over 20 ns for the ATP binding site of the DNA gyrase receptor with 5c (red) and 5f ligands (blue).
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Figure 3. Per-residue decomposition plots showing the energy contributions of compounds 5c (A) and 5f (B) to the binding and stabilization at the catalytic active site of the DNA gyrase protein receptor. Inter-molecular interactions between compounds 5c and 5f with catalytic domain binding site of DNA gyrase protein receptor are shown in subfigure (A1) and (B1), respectively.
Figure 3. Per-residue decomposition plots showing the energy contributions of compounds 5c (A) and 5f (B) to the binding and stabilization at the catalytic active site of the DNA gyrase protein receptor. Inter-molecular interactions between compounds 5c and 5f with catalytic domain binding site of DNA gyrase protein receptor are shown in subfigure (A1) and (B1), respectively.
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Figure 4. The residues of the interaction of compounds 5c (A) and 5f (B) in the catalytic site of the DNA gyrase receptor.
Figure 4. The residues of the interaction of compounds 5c (A) and 5f (B) in the catalytic site of the DNA gyrase receptor.
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Table 1. Antibacterial activities of the produced compounds.
Table 1. Antibacterial activities of the produced compounds.
EntryCpd No.Antimicrobial Activity (mm)
E. coli
ATCC 25922		S. aureus
ATCC 25923		B. subtilis
ATCC 6051		K. pneumoniae
ATCC 13883		C. albicans
ATCC 10231
12(+) 15.5 ± 0.29(+) 9.53 ± 0.29(+) 12.7 ± 0.45(+) 10.4 ± 0.26(−)
23(−)(−)(−)(−)(−)
35a(+)8.5 ± 0.2(+) 9.93 ± 0.12(+) 6.1 ± 0.2(+) 9.43 ± 0.15(−)
45b(−)(−)(−)(−)(−)
55c(+) 13.4 ± 0.29(+) 18.5 ± 0.29(+) 19.8 ± 0.25(+) 18.1 ± 0.6(−)
65d(+) 13.2 ± 0.78(+) 11.2 ± 0.21(+) 20.0 ± 0.1(+) 18.3 ± 0.4(−)
75e(−)(+) 5.1 ± 0.17(−)(−)(−)
85f(+) 16.9 ± 0.29(+) 16.0 ± 0.31(+) 20.4 ± 0.25(+) 19.9 ± 0.71(−)
95g(−)(−)(−)(−)(−)
105h(−)(−)(−)(−)(−)
115i(−)(−)(−)(−)(−)
125j(−)(−)(−)(−)(−)
135k(−)(−)(−)(−)(−)
145l(−)(−)(−)(−)(−)
15Gentamycin (10 µg/mL)(+) 12.6 ± 0.06(+) 14.3 ± 0.26(+) 23.6 ± 0.06(+) 18.4 ± 0.41(−)
Values are given as mean ± standard error.
Table 2. MIC of the most active compounds.
Table 2. MIC of the most active compounds.
EntryCpd No.Concentration
(mg/mL)		Antimicrobial Activity (mm)
E. coli
ATCC 25922		S. aureus
ATCC 25923		B. subtilis
ATCC 6051		K. pneumoniae
ATCC 13883
1210 (+) 15.5 ± 0.29(+) 9.53 ± 0.29(+)12.7 ± 0.45(+) 10.4 ± 0.26
5 (+) 6.2 ± 0.12(+) 3.1 ± 0.17(+) 5.0 ± 0.10(+) 3.4 ± 0.21
2.5 (−)(−)(−)(−)
25a10 (+) 8.5 ± 0.2(+) 9.93 ± 0.12(+) 6.1 ± 0.2(+) 9.43 ± 0.15
5 (+) 4.8 ± 0.12(+) 5.7 ± 0.2(-)(+) 4.3 ± 0.1
2.5 (−)(−)(−)(−)
35c10 (+) 13.4 ± 0.29(+) 18.5 ± 0.29(+) 19.8 ± 0.25(+) 18.1 ± 0.6
5 (+) 5.4 ± 0.12(+) 9.3 ± 0.55(+) 9.0 ± 0.26(+) 6.7 ± 0.26
2.5 (−)(−)(+) 3.0 ± 0.25(−)
45d10 (+) 13.2 ± 0.78(+) 11.2 ± 0.21(+) 20.0 ± 0.1(+) 18.3 ± 0.4
5 (+) 6.4 ± 0.15(+) 4.3 ± 0.23(+) 5.2 ± 0.42(+) 7.2 ± 0.38
2.5 (−)(−)(−)(−)
55f10 (+) 16.9 ± 0.29(+) 16.0 ± 0.31(+) 20.4 ± 0.25(+) 19.9 ± 0.71
5 (+) 8.1 ± 0.42(+) 5.7 ± 0.36(+) 8.3 ± 0.3(+)10.1 ± 0.25
2.5 (+) 3.4 ± 0.31(−)(−)(+) 4.0 ± 0.36
Values are given as mean ± standard error.
Table 3. Calculated energy binding of 5c and 5f to the DNA gyrase receptor.
Table 3. Calculated energy binding of 5c and 5f to the DNA gyrase receptor.
Energy Components (kcal/mol)
ComplexΔEvdWΔEelecΔGgasΔGsolvΔGbind
5c−44.42 ± 0.48−20.80 ± 0.37−65.22 ± 0.3035.35 ± 1.31−29.87 ± 0.48
5f−43.92 ± 0.55−5.704 ± 0.13−49.62 ± 0.2016.62 ± 0.84−32.99 ± 0.65
∆EvdW = van der Waals energy, ∆Eelec = electrostatic energy, ∆Egas = gas-phase energy, ∆Gsolv = solvation free energy, ∆Gbind = calculated total binding free energy.
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Agili, F. Novel Hydrazide Hydrazone Derivatives as Antimicrobial Agents: Design, Synthesis, and Molecular Dynamics. Processes 2024, 12, 1055. https://doi.org/10.3390/pr12061055

AMA Style

Agili F. Novel Hydrazide Hydrazone Derivatives as Antimicrobial Agents: Design, Synthesis, and Molecular Dynamics. Processes. 2024; 12(6):1055. https://doi.org/10.3390/pr12061055

Chicago/Turabian Style

Agili, Fatimah. 2024. "Novel Hydrazide Hydrazone Derivatives as Antimicrobial Agents: Design, Synthesis, and Molecular Dynamics" Processes 12, no. 6: 1055. https://doi.org/10.3390/pr12061055

APA Style

Agili, F. (2024). Novel Hydrazide Hydrazone Derivatives as Antimicrobial Agents: Design, Synthesis, and Molecular Dynamics. Processes, 12(6), 1055. https://doi.org/10.3390/pr12061055

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