The Investigation of the Synthesis, Characterization, Molecular Docking, and Pharmacokinetic Properties of New Thiocarbohydrazones Based on Schiff Bases

1. Introduction

Schiff bases are chemical compounds characterized by the presence of the imine (>C=N-) functional group. Hugo Schiff first identified these chemicals through the interaction between primary amines and aldehydes, or ketones [1]. Schiff bases are important due to their wide range of applications in biological systems [2], chemical catalysis [3], medicine and pharmacy [4], as well as chemical analysis, and emerging technologies. Schiff bases exhibit many advantageous biological activities and therapeutic effects. The properties of this substance include antibacterial [5], antimicrobial [6], anti-inflammatory [7], antiviral [8], antioxidant [9], anti-HIV [10], cytotoxic [11], antifungal [12], antituberculosis [13], anticancer [14], anthelmintic [15], antiglycation [16], antidepressant [17], and corrosion inhibition [18]. Phthalaldehyde (OPA) has many uses in the field of Schiff base production and investigation [19]. Thiocarbohydrazones are a distinct group of compounds represented by the structural formula =N–NH–C(=S) NH–N= [20]. Thiocarbohydrazones are intriguing ligand systems because of their numerous possible donor sites. Typically, they function as neutral or negatively charged ligands and form a bond with the metal via a sulfur atom and one imine nitrogen atom. This phenomenon arises from the tautomeric equilibrium between the thioketo and thioenol forms. Various variables influence this equilibrium, including the characteristics of the metal ion and its counterion, the circumstances of the reaction, the properties of the solvent, and the pH level of the medium. Extra coordination sites on the lateral substituents may change both the amount of reactants and how well they bind to different metal ions. These traits could be useful in a number of biological contexts, and being able to fine-tune the chelate's stability and properties by changing the coordinating residues of the substituents could have big effects[21,22]. They have diverse applications in the fields of biochemistry [23], pharmaceuticals [24], and industry [25,26]. These compounds exhibit a range of beneficial effects, including their ability to prevent cancer [27,28], DNA repair [28], fight against microbes [29], kill bacteria [24], combat fungal infections [29], act as antioxidants [30], destroy cells [31], inhibit viruses [32], suppress tumor growth [13], and protect against corrosion [33]. Both isatin-based thiocarbohydrazone and Schiff bases possess pharmacological and biological characteristics [34]. Antioxidants have been discovered to confer health advantages by mitigating many types of harm, such as cellular senescence, mutagenic modifications, and the formation of malignant neoplastic tissue. This is accomplished by their capacity to interact with oxygen and nitrogen species, effectively nullifying their radical impacts and therefore mitigating oxidative stress conditions [35]. Antioxidants are molecular substances that disrupt oxidation by limiting the production of free radicals or by controlling the oxidation of biodiesel via the removal of existing radicals [36].These antioxidants have phenolic functional groups in their chemical composition. The antioxidant (AH) acts by impeding the progression of the peroxide radical (ROO^.) by preventing the production of radicals in the autoxidation pathway [37]. Multiple studies have indicated that Schiff bases exhibit advantageous antioxidant characteristics as a result of the inclusion of a nitrogen atom in the azomethine group, which is located in the sp² hybrid orbit. Furthermore, Schiff bases have unshared electron pairs, making them very efficient chelating agents and prone to different reactions [25]. Assessing antioxidant activities is a way to determine the reactivity of Schiff base compounds, which have the capability to create coordination complexes with metal ions. The antioxidative activity of phenolic Schiff bases (SB-OH) is intimately linked to their ability to release hydrogen atoms. There are several ways to scavenge free radicals, which results in the creation of the corresponding phenoxy radical [38,39].

2. Materials and Methods

2.1. Materials

The chemicals and solvents used in this study were procured from reputable suppliers, namely Merck & Co., Inc., located in Kenilworth, NJ, USA, and Sigma-Aldrich Chemical Company, based in St. Louis, MO, USA.

The samples were utilized without undergoing further purification. Thin layer chromatography (TLC) using Kieselgel-60 GF254 (Merck) monitored the progress of the reaction. UV-Vis spectra and absorption data were obtained with a Shimadzu (Shimadzu Corporation, Kyoto, Japan). A Perkin Elmer Spectrum-Two FT-IR spectrometer, manufactured in the USA, was utilized for Fourier transform infrared analysis at ambient temperature. ¹H NMR and ¹³C NMR spectra (in DMSO-d₆) were taken at 25 °C using an Agilent Premium Compact spectrometer operating at 14.1 Tesla and 600 MHz. A Eurovector EA3000 (Eurovector S.r.l., Pavia, Italy) elemental analyzer was used for elemental analysis.

The TGA-DSC analysis was performed using an SDT Q-600 instrument manufactured by TA Instrument-Waters in the USA. The powder samples were subjected to heating at a rate of 10 °C/min in an alumina pan with a nitrogen gas flow rate of 50 mL/min until reaching a temperature of 1100 °C.

A molecular docking study was carried out via the Molegro Virtual Docker 6.0.1. software. Compounds were sketched through Chem-Draw Ultra 18.0, and then Chem3D 18.0 was used to improve energy minimization. The crystal structure of Jack bean urease (4GY7) was obtained from the PDB bank [40]. The binding energy for each molecule with the most suitable binding pose was transferred to the Discovery Studio imaging software to obtain the two-dimensional and three-dimensional shapes [41].

The possible effect of urease inhibition on samples and thiourea at different dosages was evaluated using the spectrophotometric technique. The inhibitory concentration (IC50: µg/mL) was displayed in Table 11. The breakdown of urea produces hypochlorite of ammonia, which nitroprusside interacts with to produce urease inhibitory activity, which was detected at 630 nm [42].

For pharmacokinetic properties, we may more effectively produce highly efficient medical structures and enhance their chemistry and biological uses by assessing their ADME and drug-likeness properties and estimating their biological activity scores. Every molecule was examined for its MW, TPSA, n-ON acceptor, and n-OHNH donor compliance. Its skin accessibility (Log Kp), blood-brain barrier permeability, soluble rate, and capacity for being taken by human gastrointestinal tissues. SwissADME (http://www.swissadme.ch/index.php) and Molsoft (https://molsoft.com) websites were used in the analyses [43].

2.2. Methods

2.2.1. Synthesis of Schiff Base-Based New Thiocarbohydrazones (1-10)

(MA = 134.13 g/mol) o-Phthalaldehyde (1,2-benzenedicarbaldehyde) (5.0 mmol) reacts with thiocarbohydrazide (5.0 mmol) (MA: 106.15 g/mol). Hydrochloric acid, acting as a catalyst, modifies the mixture and dissolves it in 100% ethyl alcohol (20 mL). It is then heated under reflux and agitated. Thin layer chromatography (TLC) is employed to track the progress of the reaction using an executive phase consisting of a mixture of n-hexane and ethyl acetate at a ratio of 4:1. The resulting product is subjected to filtration prior to cooling, followed by numerous washes with cold absolute ethyl alcohol. Subsequently, it is subjected to vacuum drying, and its structure is elucidated. The o-phthalaldehyde-derived thiocarbohydrazone (2.0 mmol) reacts with aldehyde derivatives containing different R groups (2.0 mmol). Each combination is individually modified with HCl (catalyst) and dissolved in 100% ethyl alcohol (25 mL). Next, we heat each combination separately under reflux before mixing them. Thin layer chromatography (TLC) is employed to observe the progression of the processes using an executive phase consisting of a mixture of n-hexane and ethyl acetate at a ratio of 4:1. Once the temperature has decreased in the surrounding environment, the resulting substances from the reaction are separated by filtration. They are then subjected to numerous washes using ethyl alcohol that is 100% pure. After that, the substances are dried under vacuum conditions, and their structure is determined [44,45]. The products exhibited significant yields ranging from 55% to 87% (Figure 1).

3. Results and Discussion

3.1. Physical Properties

Here are the results for the physical properties, yields, melting points, colors, and elemental analyses (Table 1 and Table 2).

3.2. Vibration Frequency Ranges

The vibrations of the substances as measured by FT-IR (Table 3). Presenting the spectral areas associated with certain chemical vibrations generated by the samples. The stretching vibration of the aldehyde group (–CHO) in the first component did not exhibit two bands at 2830–2680 cm^-1. The symmetric and asymmetric stretching vibrations of the amino group (–NH₂) were not detected in the spectral range of 3400–3150 cm^-1. Instead, we detected new stretching vibrations of the imine group around 1570–1481 cm^–1. The presence of these peaks serves as an initial indication of the effective synthesis of the materials. The stretching vibrations of ν(O–H) were recorded at a range of 3685–3678 cm⁻¹ for all compounds (1–10). The stretching vibrations of ν(–C–O) originating from the methoxy and hydroxy groups were observed in the range of 1077–1065 cm⁻¹. The vibrations of the ν(–NH) group in the thiocarbohydrazone area were detected within the range of 3272–3201 cm⁻¹. The ν(-C=S) signals of the thiocarbohydrazone region were seen at 1512–1405 cm^–1. The absorptions of the ν(–C–N) group were observed at 1199–1100 cm⁻¹.

Compound 4 displayed FT-IR emissions that corresponded to distinct functional groupings. The –NH stretching vibration was detected at 3272 cm^-1. The existence of this functional group is indicated by the appearance of the –C=N stretching vibration at 1570 cm⁻¹. Furthermore, the presence of the C=S signal in the thiocarbohydrazone area was detected at a frequency of 1512 cm⁻¹. The existence of the C–N bond was shown by the detection of the stretching vibration at 1166 cm^-1 (Figure 2). The frequency statistics for all molecules were in accordance with the published values for similar compounds [4,47,48,49].

3.3. The Interpretation of the ¹H Nuclear Magnetic Resonance Spectrum

The NMR spectra of all compounds using deuterated dimethyl sulfoxide (DMSO-d₆) as the solvent. They found that DMSO-d₆ and water exist in DMSO (HOD, H₂O) at chemical shifts of about 2.00, 2.55 (quintet), and 3.40 ppm (variable, depending on the solvent and its concentration).

Shows the chemical shifts for all compounds, excluding compound 4 (Table 4). The proton signals attributed to the imine (-CH=N) groups in compounds 1–10 were seen as singular peaks within the chemical shift ranges of 8.58–8.52 ppm. The singlet signals of the amino groups (-N₂H and -N₁H) inside the thiocarbohydrazone moiety were seen at chemical shift ranges of 11.62–10.63 and 10.66–9.74 ppm, respectively. The proton signals for the hydroxyl groups (-OH) in compounds 1–10 were seen as singlets, with chemical shifts ranging from 13.46 to 8.75 ppm. For compounds 6, 7, 8, and 10, the proton signals of the methoxy group (-OCH₃) showed a singlet at 3.79, 3.80, 3.80, and 3.83 ppm, respectively.

The H1, H3, and H4 protons showed doublet peaks at 8.01–7.88 ppm, 7.66–7.64 ppm, and 8.35–8.33 ppm, respectively. The H2 proton is coupled to the H1 and H3 protons, and the observed doublet of doublets peakes at 7.55–7.54 (J = 7.5, 1.8 Hz) ppm. The H5 proton was coupled to the H4 and H6 protons and showed triplet peaks at 7.54–7.53 (J = 8.0 Hz) ppm. The H6 proton was coupled to the H5 and H7 protons and showed a doublet of doublet peaks at 7.54–7.53 (J = 8.0, 3.0 Hz) ppm. The H7 proton was detected as a doublet peak at 7.75–7.73 ppm. The H8 proton was detected as a doublet peak at 7.60–7.57 ppm. The H9 proton was coupled to the H8 and H9 protons and showed doublet of doublets peaks at 7.44–7.42 (J = 8.1, 3.0 Hz) ppm. For compound 9, the proton signal of the methylene group (-CH₂) was observed as a doublet of doublets peaking at 4.07–4.03 (2H, dd, J = 6.2 Hz) ppm; the methyl group (-CH₃) was detected as a triplet at 1.33–1.31 (1H, t, J = 6.2 Hz) ppm.

In compound 4, the signal of imine (-CH=N) was observed as a singlet at 8.55 ppm. The -N¹H and -N²H proton signals of the thiosemicarbazone region were observed as a singlet at 10.63 ppm. Table 5 displays the chemical shifts of compound 4. Figure 3 displays the aromatic proton signals of the thiosemicarbazone ring (H1–H7), which were identified within the range of 8.35 to 7.53 ppm (please see supplementary information). These results are highly consistent with values for similar compounds [50,51,52,53,54].

3.4. The interpretation of the ¹³C Nuclear Magnetic Resonance Spectrum

The ¹³C NMR spectra of the compounds were taken in DMSO-d₆; the chemical shifts are summarized in Table 6 and Table 7, respectively. In the compounds (1–9), the aromatic C signals of the aryl ring (C1–C6) were observed between 163.4 and 111.4 ppm, and those from the terephthalaldehyde ring (C9–C10) were observed between 141.1 and 128.2 ppm.

The imine compounds 1-3 and 5-10 exhibited distinctive peaks at 150.50 and 142.08 ppm, respectively, corresponding to the –C=N (C7 and C9) functional groups. Compounds 1-3 and 5-10, respectively, exhibited notable –C=S (C8) peaks at 187.64 and 184.19 ppm in the thiosemicarbazone area. The methoxy carbon atoms (–OCH₃) in compounds 6, 7, 8, and 10 exhibited resonance between 57.64 and 56.21 ppm. Compound 9 showed a methylene carbon signal at 65.75 ppm. Please refer to the supplementary material for further details.

Compound 4 exhibited a ¹³C NMR spectrum with 10 distinct resonances, which aligns with the structure depicted in Figure 4. The thiosemicarbazone part of compound 4 showed a -C=S (C12) signal with a 194.75 ppm chemical shift. The imine compound exhibited a distinctive -C=N (C11 and C13) peak, which was detected at chemical shifts of 162.29 and 169.17 ppm, respectively. The carbon atoms (C1–C10) of the ring containing two aryl groups were identified with chemical shifts of 135.61, 137.16, 131.25, 126.59, 124.58, 133.67, 125.71, 120.10, 127.28, and 130.18 ppm, respectively. The chemical shifts of the aromatic carbon signals in the terephthalaldehyde region (C14–C16) were detected at 135.61, 127.97, and 129.38 ppm, respectively. These results are consistent with the data published for analogous substances [51,55,56,57].

3.5. Analysis of the UV–Vis Spectra

The electronic absorption spectra of the newly synthesized thiocarbohydrazones, which are derived from Schiff base derivatives (1–10), indicate that absorption bands within the wavelength range of 240–350 nm were seen in all the products produced, namely in dimethylsulfoxide. The compounds exhibit notable absorption bands in their electronic spectra, namely in the aromatic ring (C=C) and thiocarbohydrazone (C=S)–imine (CH=N) area. These bands can be attributed to transitions of a π → π * and an n → π *. All compounds exhibit π → π * type transitions of C=C on the aromatic ring within the wavelength range of 240–260 nm. The n → π * transitions of the imine C=N double bond were seen at a wavelength of 280 nm, with the exception of compound 4 which exhibited a transition at 260 nm. The spectral bands seen within the range of 310–350 nm can be attributed to the electronic transition n → π * of the thiocarbohydrazone moiety possessing the C=S group.

The thiocarbohydrazone moiety (C=S) in compound 4 exhibits 2 n → π * transitions at 310 (shoulder) and 340 nm, as seen in Figure 5. The bands observed at 260 nm (shoulder) correspond to the azomethine C=N double bond and the n → π * transitions. On the other hand, the π → π * transitions of C=C on the aromatic structure are observed at 240 nm, as depicted in Figure 5. Table 8 provides a summary of the electronic spectrum data for all the substances. The observed values align with the findings published for analogous substances [2,57,58]. Please refer to the supplementary material for further details.

3.6. Thermal Properties

Thermal properties such as onset temperature (Ton), weight loss% values, and melting point temperature (Tm) values were obtained from TGA-DSC analysis, and these values were calculated from thermal curves. The thermal analysis curve of compound 4 and the calculation results for all of them are shown in Figure 6 and Table 9, respectively. The TGA curve of compound 4 showed a single decomposition step. The step was at a temperature range of 169.43–234.47 °C, and it suited the loss of the thiocarbohydrazone group (94.39%, 8.9 mg). The Tm values of thiocarbohydrazones (1-10) were calculated as 205.26, 214.01, 241.44, 232.96, 261.42, 239.74, 231.96, 298.97, 212.59, and 295.93 C, respectively. Ton values of thiocarbohydrazones (1-10) were calculated as 195.69, 200.98, 228.08, 169.43, 236.94, 211.38, 217.53, 207.42, 200.22, and 211.37 °C, respectively. It is seen from the TGA curves in Figure 7 that all of the thiocarbohydrazones have a degradation step (between 25 and 1100 °C). The weight loss% values of Schiff bases were found to be 74.20, 58.42, 54.63, 94.39, 54.93, 58.83, 58.02, 63.82, 65.13, and 61.56%, respectively. The TGA results were evaluated according to the literature [59,60,61]. Please refer to the supplementary material for further details.

3.7. Molecular Docking and Urease Inhibition

Urease is a crucial enzyme in the metabolic system that is related to the hydrolysis of urea. It is critical to discover compounds that can control this enzyme's activity. In general, the series of samples gave high molecular docking results with the urease enzyme between -153 to -189 MolDock scores. This indicates that the interaction between these compounds and the protein proceeds smoothly. However, the highest value was recorded by compound 4 with a MolDock score of -189.

Table 10. Moldock scores and inhibition activity values (IC50: µg/mL) for the samples with the urease.

Comp.	1	2	3	4	5	6	7	8	9	10	thiourea
MolDock Score	-160	-171	-175	-189	-161	-177	-170	-153	-175	-186	-
IC50 (µg/mL)	88.11±1.95	39.00±1.17	39.86±1.04	20.79±0.68	39.89±0.40	31.28±0.00	45.78±0.40	84.97±1.07	38.01±0.37	27.11±0.00	37.13±1.38

Table 10. Moldock scores and inhibition activity values (IC50: µg/mL) for the samples with the urease.

Comp.	1	2	3	4	5	6	7	8	9	10	thiourea
MolDock Score	-160	-171	-175	-189	-161	-177	-170	-153	-175	-186	-
IC50 (µg/mL)	88.11±1.95	39.00±1.17	39.86±1.04	20.79±0.68	39.89±0.40	31.28±0.00	45.78±0.40	84.97±1.07	38.01±0.37	27.11±0.00	37.13±1.38

As for the nature of the interactions, they were as follows: the interaction of the first compound 1 with urease was produced through nine bonds as: two conventional H-bonds with GLY641 and GLU642 residues, C-H bonds with THR715, two pi-donor H-bonds with VAL640 and SER645 residues, four pi-alkyl hydrophobic interactions with ARG639, VAL640, LYS716 and MET746 residues Figure 8.

The interaction between compound 2 and urease was produced through nineteen bonds as follow; seven conventional H-bonds with VAL640, GLU642, SER421, SER421, GLY638, PRO717 and ASP730 residues, two C-H bonds with SER634 and SER421 residues, a pi-cation electrostatic interaction with LYS716, pi-anion electrostatic interaction with GLU418 residue, two pi-sulfur interactions with CYS412 and PHE838 residues, pi-pi T-shaped hydrophobic interaction with PHE838 residue, four pi-alkyl hydrophobic interactions with LEU415, VAL640, LYS716 and MET746 residues Figure 9.

The interaction between compound 3 and urease formed via eleven interactions as follow; conventional H-bond with ASP730 residue, two C-H bonds with MET637 and SER421 residues, pi-anion electrostatic interaction with GLU642 residue, two pi-sulfur interactions with MET588 and PHE838 residues, amide-pi stacked hydrophobic interaction with MET637:C, O; GLY638: N residues, four pi-alkyl hydrophobic interactions with ARG639, ARG639, LYS716 and MET746 residues Figure 10.

Compound 4 has interacted with urease within sixteen bonds as follows; four conventional H-bonds with GLY641, GLU418, SER421, and SER421 residues, C-H bond with GLY641 residue, pi-cation electrostatic interaction with GLY641 residue, two pi-anion electrostatic interactions with ASP730 and ASP730 residues, two pi-sulfur interactions with CYS412 residue, pi-pi stacked hydrophobic interaction with PHE712 residue, five pi-alkyl hydrophobic interactions with LEU415, VAL640, LYS716 and LEU415 residues Figure 11.

The interaction between compound 5 and urease via thirteen bonds as follows; four conventional H-bonds with MET746, SER421, SER421 and THR715 residues, two C-H bonds with MET746 and GLY641 residues, two pi-cation electrostatic interactions with LYS716 and ARG747 residues, pi-anion electrostatic interaction with ASP730 residue, pi-sigma interaction with LYS716 residue, three pi-alkyl hydrophobic interactions with MET746, LYS745 and ARG747 residues Figure 12.

The interaction between compound 6 and urease via thirteen bonds as follows; two conventional H-bonds with SER421 and GLU418 residues, five C-H bonds with THR715, VAL744, GLY714, GLY641 and THR715 residues, pi-cation electrostatic interaction with LYS716 residue, two pi-anion electrostatic interactions with GLU418 and ASP730 residues, pi-sigma hydrophobic interaction with LYS716 residue, pi-lone pair interaction GLY641 residue, alkyl hydrophobic interaction with ILE644 residue Figure 13.

Compound 7 has interacted with urease within fourteen bonds as follows; attractive charge (salt bridge) electrostatic interaction with GLU418 residue, attractive charge electrostatic interaction with GLU642 residue, two conventional H-bonds with GLU642 residue, two C-H bonds with GLY642 and ASP730 residues, pi-anion electrostatic interaction with PHE840 residue, pi-donor H-bond with GLY641 residue, two alkyl interactions with LYS716 and LEU839 residues, four pi-alkyl hydrophobic interactions with ARG639, VAL640, LYS716 and MET746 residues Figure 14.

The interaction between compound 8 and urease was created through twelve interactions as follows; four conventional H-bonds with MET746, SER421, THR715, and GLU418 residues, C-H bond with GLU642 residue, pi-cation electrostatic interaction with LYS716 residue, pi-anion electrostatic interaction with GLU418 residue, pi-donor H-bond with MET746 residue, pi-sigma hydrophobic interaction with LYS746 residue, pi-pi T-shaped interaction with PHE838 residue, two pi-alkyl hydrophobic interaction with PHE838 residue Figure 15.

The interaction between compound 9 and urease was generated through eleven interactions as follows; three conventional H-bonds with GLU418, GLU418, and PRO717 residues, pi-pi T-shaped hydrophobic interaction with TRP728 residue, three alkyl hydrophobic interactions with LYS716, MET746 and PRO748 residues, four pi-alkyl hydrophobic interactions with TRP728, LYS716, PRO717 and MET746 residues Figure 16.

The interaction between compound 10 and urease was created via seventeen interactions as follows; three conventional H-bonds with SER645, ARG835, and GLY641 residues, six C-H bonds with SER834, GLY641, SER834, PHE840, PRO717 and ASP730 residues, pi-anion electrostatic interaction with PHE840 residue, pi-pi stacked electrostatic interaction with PHE838 residue, two alkyl hydrophobic interactions with LYS716 and MET746 residues, four pi-alkyl hydrophobic interactions with PHE838, ARG835, LYS716 and MET746 residues Figure 17.

3.8. Pharmacokinetic Properties

Since the enzyme urease occupies a location in the human digestive system, it is natural for us to test whether our compounds have the ability to reach the digestive system and how the substances will behave within the system. Compounds were examined for adherence to MW, TPSA, n-ON receptor, and n-OHNH donors. Furthermore, the permeability level (Log Kp) in both the epidermis layer and the blood-brain barrier, as well as the solubility and absorption capacity in human gastrointestinal cells, have been evaluated for each of them (Table 11). However, our results show that the properties of all compounds were investigated in terms of MW, TPSA, H-bonds acceptors, and donors’ conformance. In addition, blood-brain barrier permeability, solubility, and the ability to be absorbed by human intestinal cells. In general, our results provide information about the synthesized molecules' absorption, distribution, metabolism and excretion. The majority of the compounds with acquired ADME parameters were found to be within acceptable boundaries and did not vary from Lipinski's rules.

Table 11. Basic physicochemical properties and computational descriptors of the screened compounds.

Comp.	Physicochemical Properties				Pharmacokinetic Properties			Drug-likeness	Lipophilicity	Solubility
	M.wt	TPSA	HBA	HBD	GI absorption	Log Kp	BBB	Druglike score	MolLogP	MolLogS (mg/L)
1	486.62	146.1	4	4	Low	-6.04	2.05	-1.27	6.55	0.17
2	518.61	202.2	6	6	Low	-6.74	1.50	-1.05	6.94	0.31
3	518.61	202.2	6	6	Low	-6.74	1.17	-0.74	5.42	1.41
4	568.73	161.74	4	4	Low	-4.87	1.03	-0.98	9.26	0.05
5	550.61	242.66	8	8	Low	-7.44	1.08	-0.64	5.91	0.74
6	587.67	220.66	8	6	Low	-7.15	1.00	-0.77	6.40	0.79
7	587.67	220.66	8	6	Low	-7.15	1.00	-0.75	7.10	0.69
8	587.67	220.66	8	6	Low	-7.15	1.00	-0.71	6.59	0.66
9	606.72	220.66	8	6	Low	-6.8	0.93	-0.40	7.59	0.72
10	638.72	239.12	10	6	Low	-7.55	0.87	-0.61	4.62	28.80
Rule	≤500	<140	<10	<5	-	-(3-5)	0-6	-	<5	-

Table 11. Basic physicochemical properties and computational descriptors of the screened compounds.

Comp.	Physicochemical Properties				Pharmacokinetic Properties			Drug-likeness	Lipophilicity	Solubility
	M.wt	TPSA	HBA	HBD	GI absorption	Log Kp	BBB	Druglike score	MolLogP	MolLogS (mg/L)
1	486.62	146.1	4	4	Low	-6.04	2.05	-1.27	6.55	0.17
2	518.61	202.2	6	6	Low	-6.74	1.50	-1.05	6.94	0.31
3	518.61	202.2	6	6	Low	-6.74	1.17	-0.74	5.42	1.41
4	568.73	161.74	4	4	Low	-4.87	1.03	-0.98	9.26	0.05
5	550.61	242.66	8	8	Low	-7.44	1.08	-0.64	5.91	0.74
6	587.67	220.66	8	6	Low	-7.15	1.00	-0.77	6.40	0.79
7	587.67	220.66	8	6	Low	-7.15	1.00	-0.75	7.10	0.69
8	587.67	220.66	8	6	Low	-7.15	1.00	-0.71	6.59	0.66
9	606.72	220.66	8	6	Low	-6.8	0.93	-0.40	7.59	0.72
10	638.72	239.12	10	6	Low	-7.55	0.87	-0.61	4.62	28.80
Rule	≤500	<140	<10	<5	-	-(3-5)	0-6	-	<5	-

4. Conclusions

The paper presents the preparation of novel thiosemicarbazones, including Schiff bases, with satisfactory yields ranging from 55% to 87%. The products underwent various characterization methods including UV–Vis, FT-IR, ¹H NMR, ¹³C NMR, elemental analyses, and TGA-DSC analyses. The results of our inhibition study aligned perfectly with the findings from the molecular docking analysis of these compounds against the urease enzyme. Compound 4 exhibited the strongest inhibition activity against the enzyme, while compounds 6 and 10 also demonstrated significant inhibition. Furthermore, the results for compounds 2, 3, 5, and 9 exhibited a remarkable similarity. This similarity was also observed when comparing the results of the molecular docking for these compounds. Based on the molecular docking results, it can be inferred that these compounds have the ability to hinder the effectiveness of urease by interacting with the enzyme. In addition, when compared to thiourea, which is considered the reference inhibitor for this enzyme, compounds 4, 6, and 10 showed higher results. On the other hand, compounds 2, 3, 5, and 9 exhibited nearly identical inhibition values to the inhibitor. Pharmacokinetic properties of compound 1 and compound 4 fall within the acceptable range according to major rules. Additionally, compound 10 exhibits the highest solubility among all tested compounds and falls within the acceptable lipophilicity range. Molecules shattered many of the established boundaries. Nevertheless, some of the findings from the ADMET investigation suggest that substances that show promise in inhibiting the tested enzyme in laboratory tests could be explored as potential drugs for treating various conditions caused by excessive urease activity.