Synthesis, Antioxidant Activity, and Structure Analysis Relationship Study of Silyl-Alkylthioetheres from 2-Mercaptobenzimidazole

Abstract

Oxidative stress results from the excessive production of reactive oxygen species (ROS), which cause cellular and molecular damage and contribute to chronic diseases. Given the recognized antioxidant potential of benzimidazole derivatives—particularly 2-mercaptobenzimidazole—this study aimed to synthesize novel organosilicon S-silylalkylthioethers (I–IV) and N-alkylsilylthioethers (1a–3f) derived from this scaffold and to evaluate their antioxidant and antibrowning properties. The S-silylalkylthioethers were obtained by reacting 2-mercaptobenzimidazole with different chloroalkylsilanes under reflux in ethanol, followed by a reaction with alkyl halides in aprotic media at room temperature to prepare the N-alkylsilylthioethers. Structural elucidation was achieved through 1D and 2D NMR and FT-IR. Antioxidant activity was assessed using DPPH, the total antioxidant capacity, and ferric-reducing assays. The results showed several derivatives with notable antioxidant responses, revealing a clear relationship between carbon chain length, logP values, organosilicon substitution patterns, and radical-scavenging efficiency. Spearman correlation analysis further confirmed that DPPH activity is inversely related to total carbon number, molecular size, molecular weight, and LogP (ρ = −0.68 to −0.73, p < 0.001) and moderately negatively correlated with N-alkyl chain length (ρ = −0.47, p = 0.027), while S-alkyl chains showed no significant effect. These findings highlight the potential of these benzimidazole–organosilicon hybrids as antioxidant candidates and demonstrate how physicochemical properties govern their reactivity and antiradical capacity.

1. Introduction

Oxidative stress is caused by the excessive generation of reactive oxygen species (ROS), including superoxide anions, hydrogen peroxide (H₂O₂), hydroxyl radicals (•OH), and singlet oxygen (¹O₂) [1]. Although ROS are normal byproducts of cellular metabolism, their accumulation disrupts redox homeostasis and leads to oxidative damage to lipids, proteins, and nucleic acids [2,3]. This imbalance is strongly associated with the onset and progression of chronic disorders such as cancer, neurodegenerative diseases, cardiovascular dysfunction, diabetes, inflammation, and accelerated aging. Consequently, the search for molecules capable of counteracting oxidative stress, like antioxidants, remains as a critical area of research [4,5].

One strategy for modulating the biological activity of small molecules involves atom replacement with elements of similar valence. In this context, substitution of carbon by silicon has been reported to improve physicochemical and biological properties in medicinal chemistry [6,7,8]. Benzimidazole derivatives have attracted increasing interest in medicinal chemistry due to their versatile biological properties, including antimicrobial, antiulcer, anticancer, antioxidant, anti-inflammatory, and antiviral activities [9,10,11]. Among them, 2-mercaptobenzimidazole has shown notable antioxidant potential, attributed to the synergistic contribution of its thiol group and benzimidazole ring, which enable radical-scavenging and metal-chelating abilities [12,13,14]. Previous in vitro studies using assays such as DPPH and ABTS have confirmed its capacity to neutralize free radicals and protect biomolecules from oxidative damage [15,16,17].

The chemical modification of benzimidazole scaffolds—particularly through the incorporation of organosilicon groups—offers an attractive strategy to modulate lipophilicity, stability, and overall biological performance. However, no studies have been reported to date on the relationship between structural variations in organosilicon-benzimidazole hybrids and antioxidant behavior [18].

Therefore, the present study aimed to synthesize new S-silylalkylthioethers and N-alkylsilylthioethers derived from 2-mercaptobenzimidazole, characterize their structures using spectroscopic techniques, and evaluate their antioxidant activity. Additionally, physicochemical parameters and molecular descriptors were analyzed to establish structure–activity relationships governing their radical-scavenging properties.

2. Results

2.1. Chemistry and Synthesis

S-alkylsilylthioethers were prepared by the S-alkyl reaction of 2-mercaptobenzimidazole with chloroalkylsilanes (Figure 1). Ramos et al. 2021 proposed this methodology [19]. N-alkylsilylthioethers derivatives were prepared by the N-alkyl reaction of S-alkylsilylthioethers with alkyl halides [20].

The target compounds were obtained via a two-step synthesis. The first step corresponded to the S-alkylation. Compounds (I–IV) were obtained with yields ranging from 65% to 90%. The second step corresponds to N-alkylation, and the synthesized compounds (1a–3e) were obtained with yields ranging from 34% to 80%. Compounds (I–IV) are soluble in chloroform, DMF, DMSO, and THF at room temperature, while the N-silylalkylthioethers (1a–4f) are soluble in chloroform, hexane, and dichlorometane at room temperature. For clarity, the substituent attached to the sulfur atom is designated as R₁, while the substituent at the N(1) position of the benzimidazole ring is denoted as R₂ (Figure 1).

One of the limiting factors of an alkylation reaction is the nature of the solvent. Tecuapa et al. 2022 [21] suggest the use of a polar protic solvent, such as ethanol (EtOH). That is recommended because of the solubility of the raw material. For example, 2-mercaptobencimidazole exhibits optimal solubility in ethanol, and its evaporation does not require high boiling temperatures, such as N, N-dimethylformamide (DMF) or dimethyl sulfoxide (DMSO) [21].

Another important factor in alkylation reactions is the type of base used. In this study, the S-alkyl reaction was carried out with sodium carbonate. Chakraborty et al. 2018 mentioned that SN2 reactions have some limitations with inorganic strong bases, such as interactions between the inorganic base and the alkyl halide [22].

One of the subproducts obtained from the reaction between an N-alkyltioether, tetrabutylammonium bromide (TBAB), and potassium carbonate in DMF was a desilytation product. The reaction was carried out via an S_N2 mechanism between the bromide ion and the silicon atom; see Howarth et al. 1995 [23]. The electropositive effect, bond length of the silicon atom, and the bromide ion source promotes a nucleophilic reaction; see Magnus et al. 1982 [24]. The bond distance between silicon and carbon is around 1.89 Å, which is longer than the carbon–carbon bond (1.54 Å). This difference in bond length makes it susceptible to heterolytic cleavage; see Howarth et al. 1995 [23].

The mechanism called desilylation involves the loss of a trimethylsilyl group. According to Magnus et al. 1982 [24], the trimethylsilyl group can react with a fluoride ion, replacing the methylene group with fluoride. In this step, the methylene carbon of the trimethylsilyl group breaks its bond with the silicon atom, generating a carbanion species. This species is stabilized by protons from the acidic conditions of the N-alkyl reaction; see Magnus et al. 1982 [24]. It has been demonstrated that acidic conditions and the presence of strong nucleophiles influence hydrolytic susceptibility of alkylsilane groups. Bulky substituents, such as triethylsilane, triphenylsilane and triisopropylsilane, are not stable and generate a hydrolytic product; see Magnus et al. 1982 [24].

2.2. Spectroscopic Characterization by NMR (¹H, ¹³C, and ²⁹Si) for the Compounds I–III and 1a–3f

The structural elucidation of the synthesized alkylsilylthioether derivatives (I–III and 1a–3f) was carried out using ¹H, ¹³C, and ²⁹Si NMR spectroscopy. The obtained spectroscopic data were in full agreement with the proposed molecular structures and confirmed the successful functionalization of the benzimidazole core.

The ¹H NMR spectra showed characteristic resonances attributable to alkyl substituents and trimethylsilane groups, consistent with N-alkylation and silyl incorporation. In particular, the signals associated with the trimethylsilane moiety, and the aliphatic chains provided clear evidence of the formation of alkylsilylthioether functionalities. These observations are in accordance with previously reported organosilicon compounds [25].

The ¹³C NMR spectra further supported the structural assignments by displaying resonances corresponding to aliphatic, silyl, and aromatic carbon environments. Signals associated with carbon atoms bonded to sulfur and nitrogen were observed in the expected regions, while the aromatic carbons of the benzimidazole ring were clearly identified. The overall ¹³C NMR patterns were consistent with those reported for related benzimidazole and organosilicon derivatives [25].

To further confirm the incorporation and coordination environment of silicon, ²⁹Si NMR spectra were recorded for all derivatives. In all cases, a single resonance characteristic of tetracoordinated silicon was observed, indicating the presence of stable organosilicon moieties within the molecular framework. Similar chemical shift behavior has been reported for organosilicon compounds bearing aliphatic [20] and aromatic substituents [26].

Complete NMR spectra and detailed signal assignments for all compounds are provided in the Supplementary Materials.

2.2.1. SwissADME Physicochemical Properties Calculation

The physicochemical properties of the synthesized derivatives were evaluated using the SwissADME tool (Swiss Institute of Bioinformatics, online platform version 1.0, 2025), and the results are presented in the Supplementary Materials. All compounds comply with Lipinski’s Rule of Five, indicating favorable drug-likeness parameters. Compounds 1a–1f: Molecular weights range from 236 to 357 g/mol. LogP values are around 3, reflecting moderate lipophilicity [27]. The number of hydrogen bond donors and acceptors is below 5, and the topological polar surface area (TPSA) is approximately 60 Ų. Compounds 2a–2f: Molecular weights range from 264 to 357 g/mol, logP values between 3.0 and 4.5, and TPSA around 50 Ų. Compounds 3a–3f: Molecular weights range from 298 to 419 g/mol, logP values between 3.5 and 4.6, and TPSA around 50 Ų. These parameters indicate that the derivatives possess physicochemical properties compatible with oral drug-likeness, while providing a consistent framework for comparing steric and electronic effects in the context of antioxidant activity.

2.2.2. Antioxidant Activity (DPPH, FRAP, and Phosphomolibdenum Method)

The antioxidant activity of the N-silylalkylthioether derivatives was evaluated using three complementary assays: DPPH radical scavenging, FRAP, and the phosphomolybdenum method. The results obtained at 4000 µM/mL are summarized in

Table 1. Antioxidant activity of N-silylalkylthioethers compounds (4000 µM/mL).

Compound	% DPPH Scavenging ± SD	% FRAP ± SD	% Total Antioxidant Capacity ± SD
MBZ	81.59 ± 2.1	0.30 ± 0.05	27.83 ± 1.4
I	14.8 ± 0.9	113.0 ± 4.1	121.89 ± 3.2
II	40.17 ± 1.5	8.6 ± 1.7	71.08 ± 2.4
III	N/A	134.09 ± 3.8	85.35 ± 2.1
IV	N/A	N/A	N/A
1a	60.7 ± 1.9	92.9 ± 3.1	95.13 ± 2.7
1b	4.7 ± 0.4	N/A	89.19 ± 1.9
1c	0.78 ± 0.2	N/A	118.1 ± 2.5
1d	N/A	N/A	108.91 ± 3.4
1e	0.78 ± 0.1	N/A	120.33 ± 3.1
2a	1.28 ± 0.3	105.4 ± 2.7	95.4 ± 2.2
2b	0.25 ± 0.1	101.2 ± 2.9	81.0 ± 2.4
2c	N/A	101.4 ± 2.1	N/A
2d	N/A	70.4 ± 2.5	N/A
2e	N/A	103.3 ± 2.9	82.8 ± 3.2
3a	N/A	N/A	94.9 ± 2.7
3b	1.27 ± 0.3	N/A	118.1 ± 3.0
3c	N/A	115.8 ± 3.0	N/A
3d	N/A	101.0 ± 2.6	N/A
3e	N/A	101.5 ± 2.8	N/A
Ferulic acid	85.3 ± 2.0	—	—

Antioxidant activity of N-silylalkylthioether compounds at 4000 µM/mL. Data are expressed as mean ± standard deviation (SD) from three independent experiments. N/A indicates no measurable activity under the tested conditions, or lack of solubility in the reaction medium.

.

In the DPPH assay, substitution at the N1 position of the benzimidazole core significantly influenced radical scavenging activity. In general, shorter alkyl chains favored DPPH scavenging, whereas longer chains led to a marked reduction in activity, suggesting a predominant hydrogen atom transfer (HAT) mechanism involving the benzimidazole N–H group. This is consistent with reports by Ramos et al. (2021), who demonstrated that the dissociation energies of N–H and S–H bonds significantly influence antioxidant performance [19].

The phosphomolybdenum assay, selected for its robustness toward lipophilic compounds, revealed measurable antioxidant capacity for several derivatives [28]. Compounds bearing methylene spacers generally exhibited higher activity than those containing propylene spacers, indicating that spacer length influences hydrogen donation or electron-transfer processes.

In the FRAP, notable differences in iron-reducing capacity were observed among the compounds. Series III derivatives showed consistently higher reducing activity, while the parent 2-mercaptobenzimidazole displayed minimal response. Aromatic substitution at N1, as observed for compound 2e, enhanced Fe³⁺ reduction, suggesting that electronic and steric factors modulate electron-transfer efficiency [29].

Overall, shorter N-alkyl chains promote HAT-based DPPH scavenging, whereas electron-balanced frameworks and aromatic substituents favor ET-based FRAP and phosphomolybdenum responses.

2.3. Structure–Activity Relationship (SAR) Analysis

As expected, the structure–activity relationship (SAR) analysis revealed that the antioxidant activity of the N-silylalkylthioether derivatives is closely linked to their physicochemical properties and topological descriptors derived from SwissADME, OCHEM, and OSIRIS. The increase in the alkyl chain attached to N1—related to the incremental rise in descriptors such as D015, D024, D124, and D128, which correlate with molecular branching, carbon-chain complexity, and the number of sp³ hybridized carbons—was associated with a progressive reduction in DPPH scavenging activity (

Table 2. Molecular descriptors used for SAR analysis of N-Silylalkylthioether compounds.

Compound	D001	D015	D017	D024	D124	D126	D128	D131	D596	D687	D728	D777
I	1.0	0.375	6	11.0	31.0	32.0	2	153.6	3.0	0	0	2.416
1a	1.0	0.4118	6	12.0	34.0	35.0	2	173.0	4.0	0	0	2.697
1b	1.0	0.444	6	13.0	37.0	38.0	2	192.8	4.0	0	0	2.968
1c	1.0	0.4737	6	14.0	40.0	41.0	2	212.9	4.0	0	0	3.232
1d	1.0	0.5000	6	15.0	43.0	44.0	2	233.3	4.0	0	0	3.488
1e	1.0	0.5833	6	19.0	55.0	56.0	2	318.0	4.0	0	0	4.451
1f	2.0	0.333	12	18.0	44.0	46.0	3	240.2	3.0	0	0	4.238

Molecular descriptors calculated using OCHEM (Mold2 algorithm) for SAR evaluation of N-silylalkylthioether compounds. Descriptors include topological indices (D001, D015, D017, D024), atom-type and connectivity parameters (D124, D126, D128), global molecular topology (D131), and higher-order structural descriptors (D596, D687, D728, D777). Values were used to correlate physicochemical variation with antioxidant activity profiles.

). This trend is consistent with SwissADME lipophilicity predictions, which indicate that increasing the length of N-alkyl chains leads to higher LogP values and reduced solvent accessibility of the pyrrolic N–H group, a key site for hydrogen atom transfer (HAT) [30]. Compounds with minimal chain elongation (e.g., 1a and 1b) display moderate DPPH scavenging activity. In contrast, compounds 1c–1e, which exhibit higher D015 and D124 values indicative of increased carbon skeleton size, showed a marked loss of activity. This trend supports the hypothesis that increased steric bulk may hinder access to potential hydrogen-donating sites, thereby reducing radical quenching efficiency.

Similarly, descriptors associated with molecular weight and the distribution of topological distances (D131, D777) demonstrated a positive relationship with the total antioxidant capacity measured by the phosphomolybdenum assay. Compounds I and III exhibited higher D131 and D777 values, indicating more extended electronic environments that favor electron transfer (ET) processes, consistent with the experimentally observed elevated molybdenum-reducing capacity. In contrast, compounds II and IV, which presented increased flexibility due to their propylene spacer (as reflected in higher rotatable-bond counts in SwissADME), showed reduced total antioxidant capacity, suggesting that greater conformational freedom may destabilize favorable ET conformers.

FRAP results correlated with OSIRIS toxicity and “drug-likeness” outputs: compounds I and III, which displayed lower predicted toxicity and balanced hydrophobic/hydrophilic profiles, exhibited the highest Fe³⁺-reducing percentages. This aligns with OCHEM-derived electronic descriptors (notably D124, D128), which indicate that these molecules possess optimized heteroatom arrangement and electronic density capable of stabilizing the Fe²⁺ species. Moreover, the enhanced FRAP activity observed in benzyl-substituted compound 2e is consistent with its increased aromatic carbon count (highlighted in Mold2 descriptors), which favors π-electron delocalization and electron donation capacity [31].

Overall, the SAR indicates that (a) short N-alkyl substituents promote HAT-dependent DPPH activity, (b) rigid and electronically enriched benzimidazole environments (molecules I and III) favor ET-dependent FRAP and phosphomolybdenum reduction, and (c) aromaticity and controlled lipophilicity enhance antioxidant potential without compromising predicted toxicity. These patterns validate the integration of in silico descriptors with experimental outcomes, strengthening the mechanistic understanding of the N-silylalkylthioether series.

To further support these SAR observations with quantitative evidence, a correlation analysis was performed between DPPH radical scavenging activity and selected molecular descriptors related to chain length, molecular size, and lipophilicity. As summarized in Supplementary Table S1, DPPH activity showed a strong and significant inverse correlation with total carbon number, molecular size index, molecular weight, and LogP (Spearman’s ρ ranging from −0.68 to −0.73, p < 0.001), confirming that increasing molecular bulk and hydrophobicity are detrimental to HAT-dependent antioxidant activity. In addition, the length of the N-alkyl chain exhibited a moderate but significant negative correlation with DPPH scavenging (ρ = −0.47, p = 0.027), whereas no significant association was observed for the S-alkyl chain length. These quantitative relationships reinforce the conclusion that short N-alkyl substituents and controlled lipophilicity are key structural requirements for preserving DPPH radical scavenging efficiency in the N-silylalkylthioether series.

2.4. Computational Study

Thus, a molecule with a donor index of 1 is expected to exhibit electron-donating behavior similar to that of a sodium atom, which is a well-established electron donor. Similarly, the acceptor index is defined using fluorine as the reference. Molecules with donor index values below 1 are considered effective electron donors, whereas those with acceptor index values above 1 are classified as strong electron acceptors. By plotting both indexes, a Donor–Acceptor Map can be created to categorize molecules based on their electron-donating or electron-accepting capabilities (Figure S56).

Donor–Acceptor Map (DAM) Analysis

Based on the indices calculated and summarized in

Table 3. Ionization energy, electron affinity, electron-donating power, electron-accepting power, electron donor index, and electron acceptor index for the molecules under study.

Molecule	I (kcal/mol)	A (kcal/mol)	ω− (kcal/mol)	ω+ (kcal/mol)	Rd	Ra
II	178.44	−30.05	76.53	2.34	0.980	0.052
2a	176.40	−29.87	75.55	2.28	0.968	0.050
2b	175.69	−29.93	75.12	2.24	0.962	0.049
2c	175.15	−29.85	74.88	2.23	0.959	0.049
2d	174.72	−29.95	74.58	2.20	0.955	0.049
2e	175.03	−26.82	76.87	2.77	0.985	0.061
2g	176.91	−26.81	77.91	2.86	0.998	0.063
I	190.45	−17.16	92.46	5.81	1.184	0.128
1a	187.59	−17.28	90.77	5.62	1.163	0.124
1b	188.00	−16.45	91.65	5.88	1.174	0.130
1c	187.93	−16.24	91.77	5.93	1.176	0.131
1d	187.35	−16.28	91.42	5.89	1.171	0.130
1e	186.18	−15.32	91.53	6.10	1.172	0.135
1g	188.78	−14.08	93.97	6.62	1.204	0.146
III	189.08	−13.08	94.94	6.94	1.216	0.153
3a	186.84	−13.36	93.46	6.72	1.197	0.148
3b	187.02	−12.87	93.96	6.89	1.203	0.152
3c	186.57	−12.94	93.65	6.84	1.200	0.151
3g	185.04	−12.29	93.33	6.95	1.195	0.153
IV	179.30	−13.35	89.27	6.29	1.143	0.139
3d	185.79	−12.97	93.20	6.78	1.194	0.150
Trolox	165.84	−38.38	64.51	0.79	0.826	0.017
Ascorbic acid	206.80	−34.64	88.82	2.74	1.138	0.060

Values were used to construct the Donor–Acceptor Map (DAM) shown in Figure 2.

, all molecules displayed R_a values well below 1, indicating a generally poor electron-accepting capacity. In contrast, molecules II to 2g exhibited R_d values below 1, classifying them as good electron donors. These compounds share the propyltrimethylsilane substituent, suggesting that this moiety significantly contributes to their electron-donating capacity and, consequently, to their antioxidant potential. Within this subgroup, a slight increase in electron-donating ability was observed as the N-alkyl chain lengthened, consistent with the trends shown in the DAM.

To deepen the analysis of the electronic structure, the highest occupied molecular orbital (HOMO) was calculated for molecules II–2g using an isovalue of 0.083, as shown in Figure 2.

There is a consistency of the HOMO being localized mainly on the imidazole ring and the S atom of this set of systems. Notably, molecule 4 does not present any orbital density on the S atom, but it is redistributed onto the benzene. These calculations suggest some sort of inducting effect from the propyltrimethylsilane moiety, synergizing with the N-alkyl substitution, which facilitates the electron donation from the mercaptobenzimidazole portion of the systems.

These electronic features reinforce the donor properties observed experimentally and help explain the correlation between molecular structure and antioxidant activity across this family of compounds.

3. Discussion

The integrated analysis of the antioxidant activity, electronic properties, and molecular descriptors of the N-silylalkylthioether derivatives demonstrates a consistent structure–activity relationship that explains the divergent behaviors observed across the series. The DPPH assay showed that compounds bearing short N-alkyl substituents (particularly 1a and, to a lesser extent, 1b) exhibited detectable radical scavenging activity, whereas elongation of the N-alkyl chain led to a pronounced decrease in scavenging capacity. This behavior, observed exclusively for compound II, may be tentatively rationalized by a hydrogen-atom transfer (HAT) contribution involving the imidazolic N–H of the benzimidazole core, whose accessibility is progressively reduced upon N-substitution, leading to diminished radical scavenging activity. SwissADME lipophilicity values and OCHEM descriptors such as D015, D024, D124, and D128 support this interpretation: increases in carbon chain complexity, branching, and topological volume strongly correlate with lower DPPH reactivity, indicating that alkyl expansion disrupts the optimal orientation needed for effective hydrogen transfer.

In contrast, the phosphomolybdenum and FRAP assays revealed that compounds I and III, which contain methylene spacers and an electronically balanced benzimidazole–thioether system, exhibit enhanced electron-transfer (ET) capacity. Their superior activity aligns with electronic descriptors (D131, D777) that reflect extended conjugation and favorable charge-distribution topology. These features likely stabilized the mentioned molecules and reduced molybdenum (V) and Fe²⁺ species, explaining their high total antioxidant capacity and iron-reducing ability. The low FRAP response of 2-mercaptobenzimidazole is also consistent with previous reports indicating that thiol-containing antioxidants show limited iron-reducing capacity due to poor detection of SH-based hydrogen donors in this method [32]. Notably, benzyl-substituted derivative 2e exhibited elevated FRAP activity, supporting the contribution of aromatic delocalization to ET-driven antioxidant behavior [33].

The electronic analysis based on ionization energy, electron affinity, and donor/acceptor indices provides further insight into the iron-reducing capacity observed in the FRAP. The Donor–Acceptor Map (DAM) revealed that all compounds exhibit R_a values well below 1, indicating intrinsically weak electron-accepting behavior. In contrast, compounds 2a–2g, together with the parent compound II, display R_d values < 1, classifying them as strong electron donors, in agreement with their enhanced FRAP responses.

The common presence of the propyltrimethylsilane substituent within this subset suggests that this moiety may contribute to a favorable inductive effect, promoting electron donation from the benzimidazole–thioether framework. This interpretation is supported by HOMO surface analysis, which shows that electron density is predominantly localized on the imidazole ring and sulfur atom—functional sites directly involved in electron transfer during Fe³⁺ reduction—while the silyl group modulates the electronic distribution without participating directly in the conjugated system [34,35,36,37,38]. An exception is compound 2c, in which HOMO density shifts toward the benzene ring, indicating that subtle structural variations can alter orbital localization and, consequently, redox behavior [34,35,36,37,38].

Toxicological screening using OSIRIS predicted low mutagenic, irritant, and tumorigenic risk for all derivatives, suggesting that the introduced structural modifications do not adversely affect safety-relevant physicochemical properties. Taken together, these results indicate that antioxidant behavior within this family arises from a delicate interplay between steric effects, electronic delocalization, and substituent-induced inductive contributions. Short alkyl chains and aromatic fragments appear to favor hydrogen-atom transfer (HAT) and electron-transfer (ET) processes, respectively, depending on the assay conditions. In this context, the propyltrimethylsilane moiety acts as an electronically modulating group that correlates with increased electron-donating character in iron-reduction-based assays (e.g., FRAP), without introducing adverse reactivity [32,39]. These findings highlight the potential of N-silylalkylthioether derivatives as versatile antioxidant scaffolds and provide a rational basis for the design of next-generation analogs with tailored redox properties [40,41,42].

The SAR and in silico analyses performed in this study provide an initial framework to understand how structural features of the synthesized N-silylalkylthioether derivatives (1a–3a) influence their physicochemical behavior, potential biological activity, and predicted safety profile. The SwissADME results revealed that all compounds comply with Lipinski’s rules and exhibit favorable molecular weights, lipophilicity, and hydrogen-bonding patterns, which are essential for oral bioavailability. These findings correlate well [8] with the molecular descriptors generated by Mold2 in OCHEM, where variations in LogP, rotatable bonds, and the proportion of sp³-hybridized carbons were associated with changes in predicted solubility and membrane permeability. Compounds with higher aliphatic carbon content and greater molecular flexibility tended to maintain adequate lipophilic–hydrophilic balance, suggesting that fine structural modifications within the N-silylalkyl chain may be used to tune drug-like properties [43,44,45].

Comparison with similar organosilicon and thioether-containing molecules reported in the literature shows consistent trends. Studies on silylated thioethers and related sulfur-containing scaffolds have demonstrated that introducing alkylsilyl groups can modulate electronic density, increase metabolic stability, and enhance lipophilicity—factors that appear to be reflected in our OSIRIS predictions, which showed low mutagenic, tumorigenic, irritant, and reproductive toxicity risks [8]. Furthermore, reports on analogous thioether derivatives indicate that sulfur-containing moieties can contribute to radical scavenging and redox-modulating effects, which aligns with the antioxidant behavior observed in our DPPH, FRAP, and phosphomolybdenum assays [46,47]. Together, these comparisons highlight that the present series shares structural and functional characteristics with previously studied bioactive thioethers, supporting their potential as promising chemical scaffolds for further pharmacological exploration [40,46,47,48,49].

Nevertheless, several limitations must be acknowledged. First, the present computational predictions do not replace experimental validation, and parameters such as metabolism, plasma protein binding, and off-target interactions require in vitro and in vivo testing. Second, while topological descriptors and drug-likeness evaluations offer valuable insights, they cannot capture the full complexity of dynamic interactions within biological systems, particularly for compounds containing silicon, a relatively underexplored element in medicinal chemistry. Third, although antioxidant capacity was experimentally evaluated, all assays were conducted at a single concentration (4000 µM), which limits the quantitative assessment of potency and precludes the determination of concentration-dependent parameters such as IC₅₀ or EC₅₀ values. Additionally, we did not evaluate the stability of the compounds under physiological conditions, where hydrolysis or oxidation could alter their activity. Finally, the dataset is limited to a small number of closely related molecules, restricting the statistical robustness of SAR observations.

Future research should build upon the present findings by integrating more advanced computational approaches, such as molecular docking, molecular dynamics simulations, and quantum chemical calculations, to elucidate the interaction patterns of these compounds with relevant biological targets. In addition, future studies should include concentration-dependent antioxidant evaluations of the most active derivatives. Expanding the chemical library through systematic modifications—varying alkylsilyl chain length, incorporating aromatic substituents, or exploring heteroatom substitutions—would enable more comprehensive SAR modeling. Experimental studies must include cytotoxicity assays, enzymatic inhibition profiles, and metabolic stability evaluations to verify the predictive models. Given the extensive literature on silicon-containing pharmaceuticals, the present results contribute to ongoing efforts aimed at elucidating how silicon substitution modulates electronic and redox properties in bioactive scaffolds. These insights may assist in the rational design of N-silylalkylthioether derivatives with balanced antioxidant performance and acceptable safety characteristics.

4. Materials and Methods

4.1. General Experimental Procedures

All chemicals were purchased from commercial suppliers as analytical grade. Melting points were recorded on the Thermo Fisher Scientific melting point apparatus (Waltham, MA, USA). The structures of all S-alkylsilylthioethers (I–IV) and N-alkylsilylthioethers (1a–3e) were confirmed using spectroscopic techniques, including FT-IR (4000–400 cm⁻¹) (Varian 3100 FT-IR spectrometer of the Excalibur series) (Silicon Valley, CA, USA). NMR (¹H, ¹³C, and ²⁹Si) spectra were recorded on a Bruker Ultra Shield Plus 400 MHz NMR spectrometer (Karlsruhe, Germany). Data for ¹H NMR spectra are reported as chemical shifts (δ ppm). The split pattern (multiplicity) is reported (s = singlet, d = doublet, q = quartet, m = multiple). ¹³C and ²⁹Si data are reported as a chemical shift (δ ppm). Reagents, including 2-mercaptobenzimidazole, chloromethyltrimethylsilane, 3-chloropropyltrimethylsilane, chloromethyldimethylphenylsilane, chloromethyldiphenylmethylsilane, iodopropane, iodide, tetrabutylammonium bromide, and silica gel 60 Å, were purchased from Sigma-Aldrich (St. Louis, MO, USA) and used without further purification. The solvents hexane and ethyl acetate used for column chromatography were distilled and stored according to standard procedures.

4.2. Reagents and Antioxidant Activity Assays

Sodium acetate buffer, 2,2-Diphenyl-1-picrylhydrazyl (DPPH), FeCl₃·6H₂O, sodium phosphate, sulfuric acid, and ammonium molybdate were obtained from Sigma-Aldrich and used without purification. Absorbance measurements were performed on a microplate ELISA reader (BMG Labtech, Ortenberg, Germany).

4.2.1. DPPH Radical Scavenging Assay

Antiradical activity was evaluated using the DPPH method with slight modifications. DPPH solution (1 mg/mL) was prepared in 12.5 mL of methanol. Stock solutions of the test compounds were prepared at 4000 µM concentration in a 1:1 DMSO:methanol mixture. For the assay, 100 µL of each compound (1a–2d) was mixed with 100 µL of DPPH solution in microplates. Ascorbic acid served as the positive control, while DMSO:methanol (1:1) was used as the negative control. Plates were incubated in the dark for 30 min, and absorbance was measured at 630 nm. The percentage of radical scavenging was calculated as follows: % scavenging = [1 − (OD sample/OD control)] × 100 [42,50].

4.2.2. Total Antioxidant Capacity (Phosphomolybdenum Method)

The total antioxidant capacity (TAC) was determined using the phosphomolybdenum method with modifications. The reagent solution contained sulfuric acid (0.6 M), NaHCO₃ (28 mM), and ammonium molybdate (4 mM) in water.

A mixture of 20 µL of each compound (1a–3a) and 180 µL of reagent solution was incubated at 95 °C for 90 min. Absorbance was recorded at 490 nm. Ascorbic acid was used as a positive control, and DMSO:methanol served as the negative control. %Antioxidant Capacity = [1 − (OD sample/OD control)] × 100 [16,51].

4.2.3. Ferric Reducing Power Assay (FRAP)

The ferric reducing capacity of compounds (1a–3a) was determined using the potassium ferricyanide–ferric chloride method, following Benzie et al. (1996) [52].

Each reaction contained 40 µL of compound stock solution, 50 µL of phosphate buffer (0.2 M, pH 6.6), and 50 µL of potassium ferricyanide (1%). The mixture was incubated at 50 °C for 20 min. Afterward, 50 µL trichloroacetic acid (10%) was added, and the mixture was centrifuged at 3000 rpm for 10 min. Supernatant (166.66 µL) was combined with 33.30 µL ferric chloride (0.1%), mixed for 1 min, and the absorbance was measured at 490 nm. Ascorbic acid was the positive control. %Ferric Reducing Capacity = [1 − (OD sample/OD control)] × 100 [51,52].

4.3. Computation Details

All molecular structures were optimized without imposing symmetry constraints using Density Functional Theory implemented in the ORCA software package (version 6.0.1) [53,54]. The PBEh-3c composite approach was employed, which uses the def2-mSVP basis set along with the Becke–Johnson dispersion correction and geometrical counterpoise correction [55,56,57]. Frequency calculations were performed to verify that all stationary points corresponded to a true minimum and confirmed that all identified energy minima corresponded to true optimized states. These optimized structures were then employed to determine the energies of the corresponding neutral, cationic, and anionic species of each system under study. Based on these values, the vertical ionization potential (I) and electron affinity (A) were calculated through the following equations: I = E_N−1 − E_N, A = E_N − E_N+1. Where $E_N$, $E_{N-1}$, and $E_{N+1}$ are the energies for the neutral, cation, and anion states of every system under study. These values were then used to calculate the electron-donating (ω⁻) and electron-accepting (ω⁺) powers [58,59], using the following formulas: ω⁻ = (3I + A)²/16(I − A) and ω⁺ = (I + 3A)²/(16(I − A). Furthermore, these powers were normalized using sodium and fluorine atoms as reference points to obtain donor (R_d) and acceptor (R_a) indices, which are defined as follows: R_d = ω⁻/(ω_Na⁻) and R_a = ω⁺/(ω_F⁺). A donor index of one indicates electron-donating behavior comparable to that of sodium, while values below one reflect effective donor character. Conversely, acceptor indices above one indicate strong electron-accepting behavior, with fluorine as the standard [60]. These normalized indices allowed the construction of a Donor–Acceptor Map to categorize the electronic behavior of all evaluated molecules.

4.4. In Silico Methods

4.4.1. SwissADME Service

The physicochemical and pharmacokinetic properties of the synthesized compounds were evaluated using the SwissADME online platform. Parameters related to Lipinski’s rule, including molecular weight, lipophilicity, hydrogen-bond donors and acceptors, topological polar surface area, and solubility, were analyzed to assess drug-likeness and ADME characteristics [30,44,61,62].

4.4.2. OCHEM Molecular Descriptors

Molecular descriptors for all compounds were calculated using the OCHEM online tool [43,63]. Descriptor calculation was performed through the Mold2 algorithm, yielding twelve topological descriptors: D001 (number of 6- membered rings (carbon atoms), D015 (number of rotatable bond fractions, D017 (number of aromatic bonds), D024 (number of carbon atoms), D124 (number of atoms in each molecule), D126 (number of bonds in each molecule), D128 (number of rings in each molecule), D131 (molecular size index), D596 (number of Sp3 carbons), D687 (number of thiol groups), D728 (number of methylene groups), D777 (LogP index), and D032 (number of silicon atoms). These chemical descriptors involve lipophilicity, the number of rotatable bonds, the fraction of sp³-hybridized carbon atoms, and the proportion of aliphatic and aromatic carbons.

4.4.3. OSIRIS Toxicological and Physicochemical Predictions

The physicochemical and toxicological properties of the compounds were predicted using the OSIRIS Property Explorer. Mutagenic, tumorigenic, irritant, and reproductive-risk parameters were assessed to identify potential toxicological concerns and to evaluate the general safety profile of the studied molecules [64].

4.5. General Procedure for the Synthesis of S-Alkylsilylthioethers (I–IV)

The synthesis of S-alkylsilylthioethers was carried out by reacting 2-mercaptobenzimidazole (1 eq, 0.5 g, 3.3 mmol) with sodium carbonate (1 eq, 0.3 g, 3.3 mmol) in anhydrous ethanol. After dissolution, the corresponding chloroalkylsilane (1 eq, 0.47 mL, 3.3 mmol) was added, and the reaction mixture was stirred under reflux for twenty-four hours (Figure 2). Reaction progress was monitored by thin-layer chromatography. Upon completion, the inorganic salt formed during the reaction was filtered, and the filtrate was poured into cold water at 0 °C to precipitate the product. The resulting white solid was collected by filtration, dried, and subsequently characterized by standard NMR techniques (proton, carbon, and silicon nuclei) and FT-IR spectroscopy.

2-(((trimethylsilyl)methyl)thio)-1H-benzo[d]imidazole (I).

White solid; yield 90% (2 g). m.p. 173 °C. IR (ν cm⁻¹): ν (=CH) 3048; (ν CH) 2953; (δ CH) 1359; (δ CH f.p.) 736, (ν Si-CH) 1264; ν C-S 596. ¹H NMR (CDCl₃, 400 MHz): δ (ppm): 0.13 (s, 9H, CH₃), 2.66 (s, 2H, CH₂), 7.55–7.58 (m, 2H, H-Ar), 7.20–7.22 (m, 2H, H-Ar). ¹³C NMR (CDCl₃, 100.62 MHz): δ (ppm): 153.9 (C2), 139.5 (C4a), 122 (C4), 113.9 (C5), 113.9 (C6), 122 (C7), 139.5 (C7a), 17.4 (C8), 1.8 (C9). ²⁹Si NMR (CDCl₃, 161.98 MHz): δ (ppm): +2.2

2-((3-(trimethylsilyl)propyl)thio)-1H-benzo[d]imidazole (II).

White solid; yield 72% (1.8 g). m.p. 163 °C. IR (ν cm⁻¹): ν (=CH) 3047; (ν CH) 2952; (δ CH) 1358; (δ CH f.p.) 736, (ν Si-CH) 1269; ν C-S 585. ¹H NMR (DMSO-d⁶), 400 MHz): δ (ppm): 0.05 (s, 9H, CH₃), 0.62 (t, 2H, CH₂), 1.7 (q, 2H, CH₂), 3.22 (t, 2H, CH₂), 7.43 (m, 2H, H-Ar), 7.09–7.11 (m, 2H, H-Ar). ¹³C NMR (CDCl₃, 100.62 MHz): δ (ppm): 150.7 (C2), 140 (C4a), 121.7 (C4), 114.1 (C5), 114.1 (C6), 121.7 (C7), 140 (C7a), 35.0 (C8), 24.7 (C9), 16 (C10), 1.24 (C11). ²⁹Si NMR (CDCl₃, 161.98 MHz): δ (ppm): +1.3.

2-(((dimethyl(phenyl)silyl)methyl)thio)-1H-benzo[d]imidazole (III).

White solid; yield 65% (1.9 g). m.p. 140 °C. IR (ν cm⁻¹): ν (=CH) 3046; (ν CH) 2951; (δ CH) 1362; (δ CH f.p.) 730, (ν Si-CH) 690–760; ν C-S 596. ¹H NMR(CDCl₃, 400 MHz): δ (ppm): 0.13 (s, 9H, CH₃), 2.66 (s, 2H, CH₂), 7.55–7.58 (m, 2H, H-Ar), 7.20–7.22 (m, 2H, H-Ar). NMR ¹³C (CDCl₃, 100.62 MHz): δ (ppm): 153.9 (C2), 139.5 (C4a), 122 (C4), 113.9 (C5), 113.9 (C6), 122 (C7), 139.5 (C7a), 17.4 (C8), 1.8 (C9). ²⁹Si NMR (CDCl₃, 161.98 MHz): δ (ppm): −3.7.

2-((3-(methyldiphenylsilyl)propyl)thio)-1H-benzo[d]imidazole (IV).

White solid; yield 65% (2.4 g). m.p. 158 °C. IR (ν cm⁻¹): ν (=CH) 3062; (ν CH) 2918; (δ CH) 1362; (δ CH f.p.) 731–762 (ν Si-CH) 1248; ν C-S 575. ¹H NMR (CDCl₃, 400 MHz): δ (ppm): 0.53 (s, 3H, CH₃), 1.20–1.24 (m, 2H, CH₂), 1.80–1.91 (m, 2H, CH₂), 3.33–3.36 (t, 2H, CH₂), 7.20–7.22 (m, 3H, H-Ar), 7.47–7.49 (m, 1H, H-Ar), 7.30–7.42 (m, 10H, H-Ar). ¹³C NMR (CDCl₃, 100.62 MHz): δ (ppm): 151.9 (C2), 143.5 (C3a), 118.2 (C4), 121.5 (C5), 121.5 (C6), 108.6 (C7), 136.7 (C7a), 35.9 (C9), 24.1 (C10), 13.6 (C11), −4.9 (C13), 136.0 (C14), 134.4 (C15), 127.7 (C16), 129.1 (C17). ²⁹Si NMR (CDCl₃, 161.98 MHz): δ (ppm): −4.6.

4.6. General Procedure for the Synthesis of N-Alkylsilylthioethers (1a–3f)

To a solution of compounds, I–IV (1 eq, 0.5 g, 2.1 mmol) in 20 mL of tetrahydrofuran (THF) was added to NaOH (1 eq, 0.08 g, 2.1 mmol) and stirred at room temperature for 24 h, followed by addition of the alkyl halide (1 eq, 0.13 mL, 2.1 mmol) dropwise. The mixture was stirred at room temperature for 48 h (Figure 3). The reaction was monitored by thin-layer chromatography. Upon completion, the reaction mixture was filtered off, and the solvent evaporated at reduced pressure. Finally, the N-alkylsilylthioether products were purified using a silica gel (60 Å) chromatographic column using a 9:1 (hexane: ethyl acetate) eluent ratio. The compounds obtained (1a–3f) were characterized by spectroscopy techniques (FT-IR, NMR ¹H, ¹³C, and ²⁹Si).

1-methyl-2-(((trimethylsilyl)methyl)thio)-1H-benzo[d]imidazole (1a). Yellow liquid; yield (69.11%). ¹H NMR (CDCl₃, 400 MHz): δ (ppm): 3.65 (s, 3H, CH₃), 0.21 (s, 9H, CH₃), 2.67 (s, 2H, CH₂), 7.20–7.26 (m, 3H, H-Ar), 7.69–7.72 (m, 1H, H-Ar). ¹³C NMR (CDCl₃, 100.62 MHz): δ (ppm): 155 (C2), 143.2 (C4a), 121.6 (C4), 108.7 (C5), 108.7 (C6), 118.2 (C7), 137.4 (C8), 16.9 (C8), 1.75 (C9), 29.8 (C10). ²⁹Si NMR (CDCl₃, 161.98 MHz): δ (ppm): +2.2.

1-ethyl-2-(((trimethylsilyl)methyl)thio)-1H-benzo[d]imidazole (1b) Yellow liquid; yield (61.71%). ¹H NMR (CDCl₃, 400 MHz): δ (ppm): 1.37 (t, 3H, CH₃), 4.09 (q, 2H, CH₂) 0.2 (s, 9H, CH₃), 2.67 (s, 2H, CH₂), 7.20–7.26 (m, 3H, H-Ar), 7.69–7.72 (m, 1H, H-Ar). ¹³C NMR (CDCl₃, 100.62 MHz): δ (ppm): 153.9 (C2), 143.5 (C4a), 121.5 (C4), 108.3 (C5), 108.3 (C6), 118 (C7), 136 (C7a), 16.8 (C8), 1.7 (C9), 38.7 (C10). ²⁹Si NMR (CDCl₃, 161.98 MHz): δ (ppm): +2.1.

1-propyl-2-(((trimethylsilyl)methyl)thio)-1H-benzo[d]imidazole (1c) Yellow liquid; yield (81.11%). ¹H NMR (CDCl₃, 400 MHz): δ (ppm): 0.97 (t, 3H, CH₃), 1.84 (m, 2H, CH₂), 4.04 (t, 2H, CH₂), 0.2 (s, 9H, CH₃), 2.68 (s, 2H, CH₂), 7.19 (m, 3H, H-Ar), 7.70–7.71 (m, 1H, H-Ar). ¹³C NMR (CDCl₃, 100.62 MHz): δ (ppm): 154.4 (C2), 143.4 (C4a), 121.5 (C4), 108.5 (C5), 108.5 (C6), 118 (C7), 136.6 (C7a), 17 (C8), 1.7 (C9), 45. 5 (C10), 22.6 (C11), 11.3 (C12). ²⁹Si NMR (CDCl₃, 161.98 MHz): δ (ppm): +2.1.

1-butyl-2-(((trimethylsilyl)methyl)thio)-1H-benzo[d]imidazole (1d) Yellow liquid; yield (80.8%). ¹H NMR (CDCl₃, 400 MHz): δ (ppm): 0.96 (t, 3H, CH₃), 1.4 (m, 2H, CH₂), 1.79 (m, 2H, CH₂), 4.07 (t, 2H, CH₂), 0.2 (s, 9H, CH₃), 2.67 (s, 2H, CH₂), 7.19–7.21 (m, 3H, H-Ar), 7.60–7.71 (m, 1H, H-Ar). ¹³C NMR (CDCl₃, 100.62 MHz): δ (ppm): 154.3 (C2), 143.5 (C4a), 121.4 (C4), 108.5 (C5), 108.5 (C6), 118 (C7), 136.6 (C7a), 17 (C8), 1.7 (C9), 43.8 (C10), 31.3 (C11), 20.1 (C12), 13.7 (C13). ²⁹Si NMR (CDCl₃, 161.98 MHz): δ (ppm): +2.2.

1-benzyl-2-(((trimethylsilyl)methyl)thio)-1H-benzo[d]imidazole (1e) White solid; yield (56.57%). ¹H NMR (CDCl₃, 400 MHz): δ (ppm): 5.31 (s, 2H, CH₂), 0.20 (s, 9H, CH₃), 2.72 (s, 2H, CH₂7.15–7.33 (m,8H, H-Ar) 7.76(m, 1H, H-Ar) ¹³C NMR (CDCl₃, 100.62 MHz): δ (ppm): 154.8 (C2), 143.4 (C4a), 121.9 (C4), 109.5 (C5), 109.5 (C6), 118.12 (C7), 136.57 (C7a), 17.3 (C8), 1.73 (C9), 47.5 (C10). ²⁹Si NMR (CDCl₃, 161.98 MHz): δ (ppm): +2.2.

1-octyl-2-(((trimethylsilyl)methyl)thio)-1H-benzo[d]imidazole (1f) Yellow liquid; yield (72.71%). ¹H NMR (CDCl₃, 400 MHz): δ (ppm): 0.21 (s, 9H, CH₃), 0.89 (t, 3H, CH₃), 1.27–1.36 (m, 10H, CH₂), 1.77–1.84 (q, 2H, CH₂), 2.68 (s, 2H, CH₂), 4.06 (s, 2H, CH₂), 7.19–7.22 (m, 3H, H-Ar), 7.69–7.72 (m,1H, H-Ar). ¹³C NMR (CDCl₃, 100.62 MHz): δ (ppm): 154.3 (C2), 143.5 (C4a), 121.4 (C4), 108.5 (C5), 108.5 (C6), 118 (C7), 136.5 (C7a), 17 (C8), 1.76 (C9), 44 (C10), 31.7 (C11), 29.2 (C12), 29.15 (C13), 29 (C14), 26.8 (C15), 22.6 (C16), 14 (C17). ²⁹Si NMR (CDCl₃, 161.98 MHz): δ (ppm): +2.2.

1-((trimethylsilyl)methyl)-2-(((trimethylsilyl)methyl)thio)-1H-benzo[d]imidazole (1g). White solid; yield (72.0%). ¹H NMR (CDCl₃, 400 MHz): δ (ppm): 3.66(s, 3H, CH₂), 0.20 (s, 9H, CH₃), 0.11 (s, 9H, CH₃), 2.67 (s, 2H, CH₂), 7.14–7.20 (m, 3H, H-Ar), 7.67–7.71 (m, 1H, H-Ar). ¹³C NMR (CDCl₃, 100.62 MHz): δ (ppm): 154.1(C2), 143.3 (C3a), 117.9 (C4), 121.2 (C5), 121.2 (C6), 108.9 (C7), 136.8 (C7a), 16.9 (C9), 17.2 (C9), −1.7 (C11), 35.4 (C12), −1.4 (C14). ²⁹Si NMR (CDCl₃, 161.98 MHz): δ (ppm): 3.5, −2.1.

1-methyl-2-((3-(trimethylsilyl)propyl)thio)-1H-benzo[d]imidazole (2a) Yellow liquid; yield (63.13%). ¹H NMR (CDCl₃, 400 MHz): δ (ppm): 3.65 (s, 3H, CH₃), 0.03 (s, 9H, CH₃), 0.70–0.74 (m, 2H, CH₂), 1.78–1.85 (m, 2H, CH₂), 3.43 (t, 2H, CH₂), 7.21–7.22 (m,3H, H-Ar), 7.69–7.71 (m, 1H, H-Ar). ¹³C NMR (CDCl₃, 100.62 MHz): δ (ppm): 150.3 (C2), 143.4 (C4a), 121.6 (C4), 108.3 (C5), 108.3 (C6), 118.1 (C7), 136.7 (C7a), 29.9 (C8), 24.4 (C9), 16.3 (C10), 1.6 (C11). ²⁹Si NMR (CDCl₃, 161.98 MHz): δ (ppm): +1.5.

1-ethyl-2-((3-(trimethylsilyl)propyl)thio)-1H-benzo[d]imidazole (2b) Yellow liquid; yield (87.3%). ¹H NMR (CDCl₃, 400 MHz): δ (ppm): 1.41 (t, 3H, CH₃), 4.18 (q, 2H, CH₂), 0.02 (s, 9H, CH₃), 0.70–0.75 (m,2H, CH₂), 1.80–1.84 (m, 2H, CH₂), 3.44 (t, 2H, CH₂), 7.21–7.28 (m, 3H, H-Ar), 7.69–7.72 (m, 1H, H-Ar). ¹³C NMR (CDCl₃, 100.62 MHz): δ (ppm): 151.7 (C2), 143.4 (C4a), 121.6 (C4), 108.4 (C5), 108.4 (C6), 118.2 (C7), 135.7 (C7a), 36 (C8), 24.3 (C9), 16.3 (C10), 1.7 (C11), 38.7 (C12), 14.4 (C13). ²⁹Si NMR (CDCl₃, 161.98 MHz): δ (ppm): +1.5.

1-propyl-2-((3-(trimethylsilyl)propyl)thio)-1H-benzo[d]imidazole (2c) Yellow liquid; yield (73.68%). ¹H NMR (CDCl₃, 400 MHz): δ (ppm): 0.99 (t, 3H, CH₃), 1.85 (m, 2H, CH₂), 4.07 (t, 2H, CH₂), 0.02 (s, 9H, CH₃), 0.77 (t, 2H, CH₂), 1.84 (m, 2H, CH₂), 3.44 (t, 2H, CH₂), 7.20–7.26 (m, 3H, H-Ar), 7.69–7.72 (m, 1H, H-Ar). ¹³C NMR (CDCl₃, 100.62 MHz): δ (ppm): 152.2 (C2), 143.6 (C4a), 121.5 (C4), 108.6 (C5), 108.6 (C6), 118.2 (C7), 136.2 (C7a), 36 (C8), 24.3 (C9), 16.3 (C10), 1.7 (C11), 45.6 (C12), 22.6 (C13), 11.3 (C14). ²⁹Si NMR (CDCl₃, 161.98 MHz): δ (ppm): +1.5.

1-butyl-2-((3-(trimethylsilyl)propyl)thio)-1H-benzo[d]imidazole (2d) Yellow liquid; yield (80.80%). ¹H NMR (CDCl₃, 400 MHz): δ (ppm): 0.95–0.97 (t, 3H, CH₃), 1.37–1.41 (m, 2H, CH₂), 1.79–1.81 (m, 2H, CH₂), 4.08 (t, 2H, CH₂), 0.03 (s, 9H, CH₃), 0.70–0.75 (m, 2H, CH₂), 3.45 (t, 2H, CH₂). 7.21–7.24 (m, 3H, H-Ar), 7.70–7.72 (m, 1H, H-Ar). ¹³C NMR (CDCl₃, 100.62 MHz): δ (ppm): 151.1 (C2), 143.6 (C4a), 121.5 (C4), 108.6 (C5), 108.6 (C6), 118.2 (C7), 136.1 (C7a), 36 (C8), 24.3 (C9), 16.3 (C10), 1.7 (C11), 43.8 (C12), 20.1 (C13), 16.3 (C14), 13.7 (C15). ²⁹Si NMR (CDCl₃, 161.98 MHz): δ (ppm): +1.5.

1-benzyl-2-((3-(trimethylsilyl)propyl)thio)-1H-benzo[d]imidazole (2e) Yellow liquid; yield (35.18%). ¹H NMR (CDCl₃, 400 MHz): δ (ppm): 0.03 (s, 9H, CH₃), 0.69–0.74 (m, 2H, CH₂), 1.78–1.86 (m, 2H, CH₂), 3.46 (t, 2H, CH₂), 5.53 (s, 2H, CH₂), 7.19–7.34 (m, 8H, H-Ar), 7.74–7.76 (m, 1H, H-Ar). ¹³C NMR (CDCl₃, 100.62 MHz): δ (ppm): 152.5 (C2), 143.7 (C4a), 121.9 (C4), 118.3 (C5), 118.3 (C6), 121.9 (C7), 136.2 (C7a), 36.3 (C8), 24.3 (C9), 16.3 (C10), 1.6 (C11), 135.8 (C12), 128.8 (C13), 127.8 (C14), 126.9 (C15). ²⁹Si NMR (CDCl₃, 161.98 MHz): δ (ppm): +1.6.

2-(((dimethyl(phenyl)silyl)methyl)thio)-1-methyl-1H-benzo[d]imidazole (3a) Yellow liquid; yield (54.1%). ¹H NMR (CDCl₃, 400 MHz): δ (ppm): 0.53 (s, 9H, CH₃), 2.94 (s, 2H, CH₂), 3.60 (s, 3H, CH₃), 7.20–7.28 (m, 3H, H-Ar), 7.42- 7.43 (m, 3H, H-Ar) 7.73–7.75 (m, 1H, H-Ar) ¹³C NMR (CDCl₃, 100.62 MHz): δ (ppm): 154.4 (C2), 143.3 (C3a), 117.9 (C4), 121.3 (C5), 121.3 (C6) 108.1 (C7), 137.1 (C7a), 16.2 (C9), −3.2 (C11), 136.3 (C12), 133.6 (C13), 127.7 (C14), 129.4 (C15), 29.3 (C16). ²⁹Si NMR (CDCl₃, 161.98 MHz): δ (ppm): −4.1.

2-(((dimethyl(phenyl)silyl)methyl)thio)-1-ethyl-1H-benzo[d]imidazole (3b). Yellow liquid; yield (87.3%). ¹H NMR (CDCl₃, 400 MHz): δ (ppm): 0.52 (s, 9H, CH₃), 1.39 (t, 3H, CH₂), 2.95 (s, 2H, CH₂), 4.11 (m, 2H, CH₂), 7.24–7.26 (m, 3H, H-Ar), 7.42- 7.43 (m, 3H, H-Ar) 7.74–7.76 (m, 1H, H-Ar) ¹³C NMR (CDCl₃, 100.62 MHz): δ (ppm): 153.6 (C2), 143.6(C3a), 118.1 (C4), 121.6 (C5), 121.6 (C6) 108.3 (C7), 136.1 (C7a), 16.3 (C9), −3.0 (C11), 136.6 (C12), 133.7 (C13), 127.9 (C14), 129.6 (C15), 38.7 (C16), 14.4 (C17). ²⁹Si NMR (CDCl₃, 161.98 MHz): δ (ppm): −3.4

2-(((dimethyl(phenyl)silyl)methyl)thio)-1-propyl-1H-benzo[d]imidazole (3c). Yellow liquid; yield (73.7%). ¹H NMR (CDCl₃, 400 MHz): δ (ppm): 0.52 (s, 6H, CH₃), 0.96–0.99 (t, 3H, CH₃), 1.84–1.85 (m, 2H, CH₂), 2.95 (s, 2H, CH₂), 4.03 (t, 2H, CH₂), 7.23–7.25 (m, 3H, H-Ar), 7.42- 7.43 (m, 3H, H-Ar), 7.64–7.66 (m, 2H, H-Ar), 7.74 (m, 1H, H-Ar). ¹³C NMR (CDCl₃, 100.62 MHz): δ (ppm): 154.1 (C2), 143.4(C3a), 118.1 (C4), 121.5 (C5), 121.5 (C6) 108.6 (C7), 136.6 (C7a), 16.4 (C9), −3.0 (C11), 136.1 (C12), 133.7 (C13), 127.9 (C14), 129.6 (C15), 45.5 (C16), 22.6 (C17), 11.4 (C18). ²⁹Si NMR (CDCl₃, 161.98 MHz): δ (ppm): −3.5.

2-(((dimethyl(phenyl)silyl)methyl)thio)-1-butyl-1H-benzo[d]imidazole (3d). Yellow liquid; yield (80.8%). ¹H NMR (CDCl₃, 400 MHz): δ (ppm): 0.52 (s, 6H, CH₃), 0.96–0.99 (t, 3H, CH₃), 1.84–1.85 (m, 2H, CH₂), 2.96 (s, 2H, CH₂), 4.03 (t, 2H, CH₂), 7.23–7.25 (m, 3H, H-Ar), 7.42- 7.43 (m, 3H, H-Ar), 7.64–7.66 (m, 2H, H-Ar), 7.74 (m, 1H, H-Ar). ¹³C NMR (CDCl₃, 100.62 MHz): δ (ppm): 154.0 (C2), 143.4(C3a), 118.1 (C4), 121.5 (C5), 121.5 (C6) 108.6 (C7), 136.6 (C7a), 16.4 (C9), −3.0 (C11), 136.5 (C12), 133.7 (C13), 127.9 (C14), 129.6 (C15), 43.8 (C16), 31.4 (C17), 20.1 (C18), 13.7 (C19). NMR de ²⁹Si (CDCl₃, 161.98 MHz): δ (ppm): −3.5.

2-(((dimethyl(phenyl)silyl)methyl)thio)-1-octyl-1H-benzo[d]imidazole (3e). Yellow liquid; yield (72.3%). ¹H NMR (CDCl₃, 400 MHz): δ (ppm): 0.50 (s, 6H, CH₃), 0.90–0.93 (t, 3H, CH₃), 1.29–1.35 (m, 10H, CH₂), 1.78–1.82 (m, 2H, CH₂), 2.93 (s, 2H, CH₂), 4.04–4.06 (t, 2H, CH₂), 7.22–7.25 (m, 3H, H-Ar), 7.41- 7.42 (m, 3H, H-Ar), 7.62–7.65 (m, 2H, H-Ar), 7.72–7.74 (m, 1H, H-Ar). ¹³C NMR (CDCl₃, 100.62 MHz): δ (ppm): 154.1 (C2), 143.4(C3a), 118.0 (C4), 121.5 (C5), 121.5 (C6) 108.6 (C7), 136.6 (C7a), 16.4 (C9), −3.0 (C11), 136.5 (C12), 133.7 (C13), 127.9 (C14), 129.6 (C15), 44.0 (C16), 31.7 (C17), 29.2 (C18), 29.16 (C19), 29.1 (C20), 26.8 (C21), 22.6 (C22), 14 (C23). ²⁹Si NMR (CDCl₃, 161.98 MHz): δ (ppm): −3.5.

1-benzyl-2-(((dimethyl(phenyl)silyl)methyl)thio)-1H-benzo[d]imidazole (3f). Yellow liquid; yield (72.3%). ¹H NMR (CDCl₃, 400 MHz): δ (ppm): 0.53 (s, 6H, CH₃), 0.90–0.93 (t, 3H, CH₃), 1.29–1.35 (m, 10H, CH₂), 1.78–1.82 (m, 2H, CH₂), 3.00 (s, 2H, CH₂), 5.27 (s, 2H, CH₂), 7.18–7.22 (m, 3H, H-Ar), 7.43- 7.45 (m, 3H, H-Ar), 7.65–7.67 (m, 2H, H-Ar), 7.80–7.82 (m, 1H, H-Ar). ¹³C NMR (CDCl₃, 100.62 MHz): δ (ppm): 154.4 (C2), 143.6 (C3a), 118.2 (C4), 121.9 (C5), 121.5 (C6) 109.1 (C7), 136.6 (C7a), 16.7 (C9), −3.0 (C11), 136.6 (C12), 113.7 (C13), 127.0 (C14), 129.6 (C15), 47.5 (C16), 128.8 (C17), 127.0 (C18), 128.0 (C19), 127.9 (C20). ²⁹Si NMR (CDCl₃, 161.98 MHz): δ (ppm): −3.8.

4.7. Statistical Analysis

Experimental data are expressed as mean ± standard deviation (SD) from at least three independent measurements. Correlation analyses between structural features, physicochemical descriptors, and antioxidant activity were performed using Spearman’s rank correlation coefficient. All statistical analyses were carried out using SPSS software (IBM Corp., Armonk, NY, USA) version 27.0.

5. Conclusions

In this work, a straightforward and modular synthetic approach was developed to access a series of silyl-thiomercaptobenzimidazole derivatives, based on the nucleophilic substitution of 2-mercaptobenzimidazole followed by N-alkylation with alkylsilyl fragments. The synthesized compounds were subsequently evaluated for antioxidant activity using complementary in vitro assays. The results reveal a structure–activity relationship governing the redox behavior of N-silylalkylthioether derivatives, arising from the combined influence of steric effects, electronic delocalization, and substituent-induced inductive contributions. Notably, measurable hydrogen-atom transfer (HAT) activity in the DPPH assay was observed only for compound II, which retains an unsubstituted benzimidazole N–H group, whereas N-alkylation led to a pronounced loss of radical scavenging ability. In contrast, aromatic substitution and electronically balanced frameworks favored electron-transfer (ET) processes, as reflected in the FRAP and phosphomolybdenum assays.

Computational analyses further indicate that the propyltrimethylsilane substituent modulates the electronic environment of the benzimidazole–thioether scaffold, correlating with increased electron-donating character in iron-reduction-based assays, without directly participating in conjugation or adversely affecting safety-relevant physicochemical properties. All compounds exhibited favorable drug-likeness parameters and low predicted toxicity, supporting their potential as tunable antioxidant scaffolds. Collectively, these findings provide a rational basis for the design of improved N-silylalkylthioether analogs and support further investigation of organosilicon–sulfur hybrids within established medicinal chemistry frameworks.