Abstract
Context
This study addresses the development of sustainable pyridinium ionic liquids (ILs) because of their potential applications in agriculture and pharmaceuticals. Pyridinium-based ILs are known for their low melting points, high thermal stability, and moderate solvation properties. We synthesized three novel pyridinium-based ILs: 1-(2-(isopentyloxy)-2-oxoethyl)pyridin-1-ium chloride, 1-(2-(hexyloxy)-2-oxoethyl)pyridin-1-ium chloride, and 1-(2-(benzyloxy)-2-oxoethyl)pyridin-1-ium chloride. The biological activities of these compounds were evaluated through plant growth promotion, herbicidal, and insecticidal assays. Our results show that the benzyloxy derivative significantly enhances wheat and cucumber growth, whereas the isopentyloxy compound has potent herbicidal effects. Computational methods, including DFT calculations and molecular docking, were applied to understand the structure‒activity relationships (SARs) and mechanisms of action.
Methods
The computational techniques involved dispersion-corrected density functional theory (DFT) with the B3LYP functional and the 6-311G** basis set. Grimme’s D3 corrections were included to account for dispersion interactions. The calculations were performed via GAMESS-US software. Quantum descriptors of reactivity, such as ionization potential, electron affinity, chemical potential, and electrophilicity index, were derived from the HOMO and LUMO energies. Molecular docking studies were conducted via the CB-Dock server via AutoDock Vina software to predict binding affinities to cancer-related proteins. Petra/Osiris/Molinspiration (POM) analysis was used to predict the drug likeness and other pharmaceutical properties of the synthesized ILs.
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Introduction
Ionic liquids (ILs) are organic salts with melting points below 100 °C that exhibit desirable properties such as low volatility, nonflammability, and good solvation capabilities. Ionic liquids (ILs) have garnered significant attention for their diverse applications in green chemistry, catalysis, separations, and, more recently, as biologically active agents. Conventional ILs typically consist of imidazolium, pyridinium, or pyridinium cations paired with various organic anions. Nonetheless, the exploration of alternative ionic structures is still needed to enhance the physical and chemical characteristics of ILs. Quaternary pyridinium salts represent a subclass of ILs distinguished by a tetrasubstituted pyridinium cation. Previous studies have shown that organic substituents notably affect biological activity [1,2,3]. In other words, quaternary pyridinium compounds (QACs) exhibit antimicrobial, herbicidal, and plant growth regulatory properties attributed to their cationic charge and hydrophobic domains. Nevertheless, the rational design of new QACs with well-defined structure‒activity relationships (SARs) remains an ongoing challenge [4,5,6].
The exploration of novel cation and anion combinations remains an active research endeavor aimed at discovering ILs with tailored physicochemical characteristics and specialized functions. The organic substituents attached to the central nitrogen atom can be systematically modified to adjust the physical and electronic properties and introduce biological activities [7,8,9]. Prior studies have demonstrated that quaternary pyridinium compounds (QACs) possess potent antibacterial, antifungal, and herbicidal properties due to their amphiphilic nature. These cationic surfactants are known to interact with microbial and plant cell membranes followed by their disruption. Structural modifications affecting lipophilicity, hydrogen bonding, and steric effects can influence the mechanism of the biological activity of ILs [10,11,12,13]. Consequently, interest in developing environmentally friendly agrochemicals, disinfectants, and pharmaceuticals with rationally designed ILs as biodegradable active ingredients is increasing [14,15,16,17]. The unique reactivity of pyridine, attributed to its weaker basicity than that of aliphatic amines, facilitates the synthesis of ILs and enhances structure‒activity relationship (SAR) studies. While aliphatic amines can also be converted into corresponding ILs and subjected to SAR analysis, the aromatic structure and electron configuration of pyridine allow for more controlled reactions and nuanced modifications, which are essential for exploring diverse chemical interactions and optimizing the performance of ILs. Previous computational investigations have employed methods such as density functional theory (DFT) calculations, quantitative structure‒activity relationship (QSAR) modeling, and molecular docking to examine ionic liquid structures, reactivity, and mechanisms of action. However, an integrated experimental‒computational approach is needed to comprehensively elucidate SARs and guide new designs [18,19,20,21,22].
In this study, the synthesis, characterization, and evaluation of novel pyridinium-based ionic liquids as potential biologically active agents are presented. Three quaternary pyridinium salts were prepared by reacting pyridine with different esters of monochloroacetic acid. The structures were analyzed via infrared spectroscopy and NMR techniques. Biological assays were subsequently used to assess their growth-promoting, herbicidal, and insecticidal effects across a range of plant and pest models. Computational methods, including density functional theory (DFT) calculations, molecular docking, and drug likeness prediction, have also been applied to gain insights into electronic properties, binding interactions, and mechanisms of action. Overall, this integrated experimental-computational study aims to provide valuable SAR knowledge for the rational design of next-generation natural ILs as agrochemical and pharmaceutical leads.
Materials and methods
Materials
Pyridine (99%), hexanol (99%), benzyl alcohol (99%), monochloroacetic acid (97%), 3-methyl-pentanol (98%), ethyl acetate (99%), ethanol (96%), and acetone (99%) were purchased from Sigma‒Aldrich.
Synthesis of quaternary pyridinium salts
The appropriate ester of monochloroacetic acid (2 mol) was added to a solution of pyridine (1 mol) in ethanol (10 mL). The reaction mixture was heated at 50–60 °C for 3 h. Upon completion, the reaction solvent was removed under reduced pressure. The residue was recrystallized from ethanol to obtain the pure quaternary pyridinium salt product.
Spectral analysis
IR spectra were obtained on a SPECORD-75IR spectrophotometer using KBr disks. 1H NMR spectra were recorded on a Unity 400 plus spectrometer operating at 400 MHz for 1H. Deuterated methanol (CD3OD) was used as the solvent, and hexamethyldisiloxane (HMDSO) was used as the internal standard.
Research methodology for assessing biological activity
Growth-promoting activity
To assess growth-promoting activity, wheat and cucumber seeds were germinated under controlled environmental conditions. Solutions of the test quaternary pyridinium salts ranging from 0.0001 to 0.1% in concentration as well as a Floroxan positive control at 0.00001% were prepared. Seeds were treated with 200 μL of each solution or a water control [23]. After a set growth period, the seedling root length, stem height, and growth percentage were measured and compared with those of the controls. Each treatment was replicated four times, and the results are reported as the means.
Herbicidal activity
To evaluate herbicidal activity, wheat and cucumber seeds were planted in soil in a growth chamber. Solutions of the test compounds from 0.1 to 0.00001% and the herbicide standards Fusilade and Stomp were prepared. To prepare test solutions of quaternary pyridinium salts ranging from 1, 0.1, and 0.01%, the salts were accurately weighed and dissolved in an appropriate solvent (distilled water) to maintain osmotic balance. The solution can be prepared via the formula \(\text{Concentration }\left(\text{\%}\right)= \left(\frac{\text{Mass of compound }(\text{g})}{\text{Volume of solution }(\text{L})}\right)\times 100\), followed by thorough mixing. The prepared solutions should be stored under refrigeration, labeled with concentration and preparation data, and equilibrated to the assay temperature before use. The plant foliage was sprayed with 200 μL of each solution at the defined concentrations. Seedling root and stem development was then assessed, and the percentages of growth inhibition compared with those of the controls were determined. Each treatment was replicated four times to obtain average results [24, 25].
Insecticidal activity
To test insecticidal activity, C. maculatus insects were reared under controlled temperature and lighting conditions for use in bioassays. Test compound solutions ranging from 1 to 0.01% along with a BAGIRA control ranging from 0.1 to 0.01% were prepared. The Petri dishes were treated with 200-μL doses and 20 insects per dish. Mortality was recorded at 24 h, and biological activity was calculated via Abbott’s formula. Each treatment was replicated four times, and the results are expressed as the mean mortality percentage.
This ensured consistent and quantifiable evaluation of the various biological activities of the novel compounds.
Computational details
Dispersion-corrected density functional theory (DFT) was combined with a molecular docking study and Petra/Osiris/Molinspiration (POM) analysis to investigate the structures and biological activities of the three considered molecules. The optimal geometries of all the molecules were determined with the B3LYP exchange-corrected functional and the 6-311G** electronic basis set. The 6-311G** basis set was selected for its balance between computational cost and accuracy. This basis set is known to provide reliable results for optimizing the geometries and calculating the electronic properties of organic molecules such as pyridinium salts [26,27,28]. It includes polarization functions on both hydrogen and heavier atoms, allowing it to account for the electron density distribution more accurately, particularly in systems where subtle interactions such as hydrogen bonding and noncovalent interactions play an important role [29,30,31]. Given the nature of our compounds and the need for precise electronic property predictions, 6-311G was a suitable choice for this study. Grimme’s D3 corrections were taken into account. GAMESS-US software was used for all the DFT calculations. The ionization potential (IP) and electron affinity (EA) were derived from the HOMO and LUMO frontier molecular orbitals according to empirical formulas based on Koopmans’s theorem [32]:
After the IP and EA values were obtained, quantum descriptors of reactivity, such as electronegativity (χ), chemical potential (μ), chemical hardness (η) and softness (S), electrophilicity (ω) and nucleophilicity (ε) indices, and electrodonating (ω–) and electroaccepting (ω+) powers, were calculated. These descriptors were calculated with the following well-known formulas:
In molecular docking, the choice of target protein depends on the specific biological activity or pathway of interest. Typically, proteins involved in the disease or biological process of interest are selected. For example, if the goal is to investigate anticancer properties, proteins implicated in cancer cell signaling or proliferation (e.g., kinases, receptors, enzymes) are targeted. For this study, proteins relevant to cancer pathways such as breast, liver, and lung cancers were selected. The selection process is guided by literature research; databases such as the Protein Data Bank (PDB); and prior studies that have demonstrated the involvement of these proteins in the biological activities being investigated, such as herbicidal, insecticidal, or pharmaceutical applications [33,34,35,36,37]. To gain additional insight into the biological activity of the considered molecules, their docking with several cancer-related proteins was investigated. For this purpose, the CB-Dock server was applied on the basis of the popular AutoDock Vina software [38]. The value of the association constant Ka for ligand‒protein docking was also estimated. Although the calculated Vina score (VS) should not be associated with the Gibbs energy of the docking process, the Ka value can be roughly estimated from the VS, as described in [39,40,41]:
where R = 1.987·10–3 kcal/(mol·K) is Boltzmann’s constant, and T = 309.75 K is the normal temperature of the human body.
The following protocol was used for molecular docking:
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Protein preparation: Target proteins were retrieved from the PDB, with nonessential water molecules and ligands removed. The energy of the proteins was minimized via appropriate force fields.
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Ligand preparation: Pyridinium salts were optimized via DFT to ensure stable geometries.
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Docking setup: Docking was performed via the CB-Dock server via AutoDock Vina, with docking grids set around the binding pockets.
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Docking parameters: Default parameters were applied for grid spacing, number of runs, and exhaustiveness.
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Analysis: Binding affinities and ligand‒protein interactions were evaluated on the basis of docking scores and interaction types (e.g., hydrogen bonds and hydrophobic contacts).
The pharmaceutical potential of the considered molecules was also predicted via Petra/Osiris/Molinspiration (POM) analysis, which is commonly applied to novel molecules that can potentially be used as drugs [42].
Results and discussion
Experimental part and spectroscopic analysis
Synthesis of corresponding esters of chloroacetic acid
The synthesis of corresponding esters of chloroacetic acid involves reacting pyridine with different esters of monochloroacetic acid to form three distinct quaternary pyridinium salts. In this procedure, an appropriate ester of monochloroacetic acid (2 mol) is added to a solution of pyridine (1 mol) in ethanol (10 mL), maintaining a molar ratio of ester to pyridine of 2:1. The reaction mixture was then heated at 50–60 °C for 3 h to ensure that the reaction was complete. Following the reaction, the ethanol solvent was removed under reduced pressure to obtain the crude product, which was subsequently purified by recrystallization from ethanol, yielding the pure quaternary pyridinium salt. This method capitalizes on the reactivity of pyridine and the acylating potential of chloroacetic acid derivatives, focusing on controlled conditions to achieve high purity and yield of the final product.
1-(2-(Isopentyloxy)-2-oxoethyl)pyridin-1-ium chloride was obtained from the reaction between pyridine and 3-methyl-pentyl ester of monochloroacetic acid. The yield of 1-(2-(isopentyloxy)-2-oxoethyl)pyridin-1-ium chloride formed in the reaction is found to be 84% (5.11 g), melting point = 217 °C.
IR analysis
The broad bands between 3337 and 3160 cm−1 correspond to O-H and/or N-H stretching vibrations. The presence of hydrogen-bonding functional groups is indicated. The signals located at 3292 and 3012 cm−1 can be assigned to aliphatic C-H stretching vibrations from the isopentyl group. The absorbances placed at 1668, 1637, and 1616 cm−1 are correspond to C=O stretching of the ester carbonyl and C=C/C=N stretches within the pyridinium ring. The peak observed at 1398 cm−1 is assigned to C-N stretching, while the band at 1093 cm−1 involves C-O stretching of the ester linkage. The 766 cm−1 band corresponds to out-of-plane C-H bending vibrations. The 684 cm−1 peak is assigned to pyridinium ring deformation. The absorbance at 636 cm−1 indicates C-C-C bending of the isopentyl substituent. Overall, the IR spectrum is consistent with the presence of the major functional groups expected in 1-(2-(isopentyloxy)-2-oxoethyl)pyridin-1-ium chloride, supporting its proposed structure (Fig. S1).
Synthesis of chloroacetic acid esters
1-(2-(Hexyloxy)-2-oxoethyl)pyridin-1-ium chloride was obtained from the reaction of pyridine with hexyl ester of monochloroacetic acid. The product yield is calculated as 80% (2.57 g), melting point = 211 °C.
IR spectral analysis
The bands at 3066 and 3336 cm−1 can be assigned to aromatic C-H stretches from the aromatic ring. The peaks between 2573 and 2407 cm−1 correspond to ammonium ion, indicative of hydrogen bonding. The strong absorbance at 1726 cm−1 is attributed to the carbonyl C=O stretch of the ester group. The band at 1636 cm−1 represents aromatic C=C stretching vibrations within the benzyl ring. The peak at 1490 cm−1 involves C-C stretches of the benzene ring. The signal at 1398 cm−1 corresponds to C-N stretching of the pyridinium moiety (Fig. S2). In the fingerprint region, the band at 1199 cm−1 is assigned to the asymmetric stretching vibrations of C–O–C ester bonds. The bands at 818 and 779 cm−1 correspond to the out-of-plane bending vibrations of aromatic C-H groups, and the band at 694 cm−1 to the bending vibrations of pyridinium ring. Overall, the IR data is consistent with the expected functional groups of 1-(2-(benzyloxy)-2-oxoethyl)pyridin-1-ium chloride like the ester carbonyl, pyridinium, benzyl ring, and hydrogen bonding motifs.
Structure (a), HOMO (b), and LUMO (c) frontier orbitals and electrostatic potential (d) of 1-(2-(isopentyloxy)-2-oxoethyl)pyridin-1-ium. The blue arrow indicates the direction of the dipole moment. Brown, white, blue, and red balls represent carbon, hydrogen, nitrogen, and oxygen atoms, respectively
1-(2-(Benzyloxy)-2-oxoethyl)pyridin-1-ium chloride was obtained from the reaction of pyridine with benzyl ester of monochloroacetic acid. The product yield is measured as 81% (2.66 g), melting point = 209 °C.
IR spectral analysis
The broad bands between 3664 and 3130 cm−1 correspond to ammonium ions stretching vibrations, suggesting hydrogen bonding. The peaks at 2962 and 2897 cm−1 are attributed to C-H stretches of the aliphatic methylene groups. The signals at 1492 and 1456 cm−1 involve aromatic C=C stretches of the benzene ring. The band at 1396 cm−1 corresponds to C-N stretching of the pyridinium moiety (Fig. S3). In the fingerprint region: 989 cm−1 = C-O-C asymmetric stretch of the ester; 854, 815 cm−1 = aromatic C-H out-of-plane bends; 777, 731 cm−1 = pyridinium ring deformation; 704, 669 cm−1 = methylene C-H bends; 459 cm−1 = C-C stretches. Overall, the IR absorptions are consistent with the key structural elements of 1-(2-(benzyloxy)-2-oxoethyl)pyridin-1-ium chloride such as the ester, benzene ring, pyridinium, and presence of hydrogen bonding. This supports the proposed identity of the synthesized compound.
Structure (a), HOMO (b), and LUMO (c) frontier orbitals and electrostatic potential (d) of 1-(2-(hexyloxy)-2-oxoethyl)pyridin-1-ium. The blue arrow indicates the direction of the dipole moment. Brown, white, blue, and red balls represent carbon, hydrogen, nitrogen, and oxygen atoms, respectively
Synthesis methodology analysis: Reaction optimization
This research investigated in depth the experimental optimization for a reaction between monochloroacetic acid esters and pyridine. These reactions are carried out to produce quaternary pyridinium salts. Three distinct solvents, ethanol, acetone, and ethyl acetate, were used to carry out the reactions since solvents can affect the reaction rate, selectivity, and yield. According to the generic chemical reaction diagram in Fig. 1, monochloroacetic acid esters (R) combine with pyridine to produce quaternary pyridinium ions. Three chloroacetic esters comprising 3-methylpentyl (-C5H11), hexyl (-C6H13), and benzyl (C6H5CH2-) groups were employed in the investigation. The synthesis of several quaternary pyridinium salts comprising ester groups in different solvents allowed us to find optimal conditions for the preparation of these compounds.
The results show the effects of temperature (30–40, 50–60, and 80–90 °C) on the yield of reacting pyridine and monochloroacetic acid esters (1:2 ratio). These reactions are exothermic processes. The highest yields (78–86%) occurred at a temperature of 50–60 °C, most likely owing to nonside reactions. The temperature affects the reaction yield by influencing the reaction rate and minimizing side reactions. Higher temperatures can increase the rate but also lead to degradation, while moderate temperatures (50–60 °C) optimized the yield in our reactions (Table 1).
The optimal reaction temperature for the quaternization of pyridine has been determined to be 50–60 °C. This is primarily because pyridine, which is known to be a weaker base than aliphatic amines, can effectively form quaternary salts at these moderate temperatures, contrary to the typically higher temperatures required for aliphatic amines. This reaction efficiency at lower temperatures is attributed to the lower basic strength of pyridine, which, while requiring more controlled conditions, avoids the need for excessive heating, which could lead to degradation. Furthermore, as indicated by the results presented in Table 2, the yield of the reaction significantly improved with increasing molar ratio of chloroacetate to pyridine. Specifically, a 1:2 ratio of pyridine to ester yielded the highest product amounts, between 76 and 81%, whereas a stoichiometric ratio of 1:1 or a higher pyridine concentration at a 1:1.5 ratio resulted in lower yields, ranging from 63 to 75%. Therefore, maintaining the reaction temperature within 50–60 °C and utilizing a molar ratio of 1:2 are optimal for achieving the highest yields of the ionic liquid.
Table 3 presents the relationship between the reaction time and yield. Contrary to initial expectations, increasing the length of the chloroacetic acid ester substituent—ranging from isopentyl to benzyl—does not significantly alter the yield, suggesting that differences in substituent size are not a major factor affecting yield. This observation is corroborated by the data in Table 3, which shows minimal variation in yield despite changes in the ester substituent size. It appears that partial solubility issues in excess pyridine, rather than substituent size, may influence the yield, particularly at higher ester concentrations. The most consistent yields, ranging from 80 to 84%, were observed with a reaction time of 3 h across all the substrates. Both shorter (2 h) and longer (4 h) reaction durations resulted in lower yields, indicating that a 3-h period is optimal for completing the reaction before side reactions occur. The optimal molar ratio identified was 1:2, and extending the reaction time beyond 3 h or adjusting the molar ratio did not further improve or even reduce the yields. These findings emphasize the importance of carefully controlling both the molar ratio and the reaction timing to optimize the formation of these quaternary pyridinium salts.
The effect of the solvent on the reaction yield was studied. Table 4 lists the effects of various solvents on the reactivity of pyridine with various monochloroacetic acid esters. Compared with solvents, ethanol provided the highest yields, ranging from 78 to 84%. On the basis of these results, the optimal conditions were identified as a 1:2 molar ratio of reactants, a temperature of 60 °C, and a reaction time of 3 h when ethanol was used as the solvent. Table 5 confirms that applying these optimized parameters to reactions between pyridine, 3-methyl-pentyl, hexyl, and benzyl esters resulted in high yields ranging from 80 to 84%. To purify the products, the salts were recrystallized from ethanol containing chloroacetic acid after heating, carbon treatment and filtration. This process yielded pure white salts. The purity of each salt was then assessed via thin-layer chromatography. Further characterization included determining the physical properties and investigating the structure.
Study of the biological activity of pyridinium salts
Growth-promoting activity
The growth-promoting activity of the novel quaternary pyridinium salts was evaluated toward wheat and cucumber seeds via standardized growth assays (Table 6). Among the test compounds evaluated, 1-(2-(benzyloxy)-2-oxoethyl)pyridin-1-ium chloride resulted in the most notable and consistent increase in both wheat and cucumber growth compared with that of the control groups. This effect was distinctly characterized by a lucid dose‒dependent response, with enhancements surpassing the 20% threshold in the concentration range of 0.0001–0.001%. In contrast, 1-(2-(isopentyloxy)-2-oxoethyl)pyridin-1-ium chloride and 1-(2-hexyloxy)-2-oxoethyl)pyridinium chloride inhibited the growth of roots and shoots. However, pyridinium salts with hexyl radicals had a positive effect on cucumber sprout growth parameters at a concentration of 0.0001% (Table 6). Overall, 1-(2-(benzyloxy)-2-oxoethyl)pyridin-1-ium chloride closely replicated the concentration-dependent activity profile of floxan, making it the most promising candidate for advancing plant development across a comprehensive array of assays. The results obtained indicate the need for further study of this class of compounds as potential plant growth regulators. The structure of the substituent in the ether of such pyridinium salts has a great influence on their biological activity. The presence of an aromatic benzyloxy moiety within the compound emerged as a significant advantage, highlighting its pivotal role in facilitating interactions with plant systems. This pattern mirrors the behavior of floxan, which also integrates an aromatic domain within its molecular structure. Furthermore, elevated doses of isopentyloxy resulted in substantial growth inhibition, potentially attributed to excess lipophilicity leading to membrane disruption. The lengths of the isopentyl and benzyl substituents are approximately the same, and the length of the hexyl radical is only slightly longer. To study the effect of a substituent in the ether group on the biological activity of pyridinium salts, it is necessary to use compounds that differ significantly in the size of the alkyl radical. In this study, both 1-(2-(hexyloxy)-2-oxoethyl)pyridin-1-ium chloride and 1-(2-(isopentyloxy)-2-oxoethyl)pyridin-1-ium chloride inhibited plant growth in the concentration range of 0.001–0.1%. A growth-stimulating effect on cucumber sprouts was established only at a 1-(2-(hexyloxy)-2-oxoethyl)pyridin-1-ium chloride concentration of 0.0001%. The growth-promoting activity is likely due to the aromatic benzyloxy group, which enhances interactions with plant systems, promoting cell growth. Consequently, it is clear that achieving an optimal balance in the lipophilic/hydrophilic character of the oxyalkyl chain, concomitant with a judicious emphasis on its hydrogen-bonding potential, stands out as a critical determinant governing the stimulation of plant development.
Herbicidal activity
The herbicidal activity of the novel quaternary pyridinium salts was rigorously assessed through wheat and cucumber seed bioassays. The commercial herbicide standards, Fusilade and Stomp, exhibited the expected robust inhibition of plant growth, serving as exemplary positive controls (Table 7). Within this context, the bioassay results revealed that 1-(2-(isopentyloxy)-2-oxoethyl)pyridin-1-ium chloride had a potent herbicidal effect, significantly reducing root and stem length by more than 80% at higher doses for both plant species, thus aligning with the results of the controls. This underscores its remarkable contact herbicidal properties. Moreover, 1-(2-(hexyloxy)-2-oxoethyl)pyridin-1-ium chloride also inhibited growth in a dose-dependent manner, albeit to a lesser extent than its isopentyloxy counterpart. Conversely, 1-(2-(benzyloxy)-2-oxoethyl)pyridin-1-ium chloride had a pronounced growth-promoting effect on the studied plants, as noted earlier. This observation implies that the modification of the oxyalkyl substituent has the potential to finely modulate the herbicidal activity profile. The concise isopentyloxy chain appears to strongly disrupt plant cell functions, particularly affecting membranes, whereas the benzyloxy variant has a milder impact. These quaternary salts likely facilitate herbicidal action by disrupting vital plant cell processes [11]. The incorporation of the ester linkage enhances their uptake, whereas the nature of the oxyalkyl chain significantly influences lipophilicity and membrane interactions. While the ether substituents of the studied compounds vary minimally in length, notable differences in their structure—such as branching—significantly influence their physicochemical properties and herbicidal activities. Compounds with shorter, branched chains, such as isopentyloxy, tend to show increased lipophilicity and more potent herbicidal properties, possibly due to their increased ability to cause nonspecific membrane damage. Conversely, compounds with marginally longer but less branched chains, such as hexyloxy and benzyloxy derivatives, exhibit lower lipophilicity and a more selective mode of herbicidal action. These findings suggest that subtle structural variations, particularly in terms of branching, rather than chain length alone, play a critical role in determining a compound’s interaction with plant membranes and its herbicidal efficacy. The lack of growth inhibition by the benzyloxy derivative suggests specific target interactions, as opposed to broader membrane effects. The pursuit of structure–activity optimization holds the promise of yielding natural herbicides tailored to target specialized biochemical pathways, facilitating precise and selective weed control. This elucidation of structure-based mechanisms of action serves as a guiding beacon for future modifications in this domain. The herbicidal activity is attributed primarily to the isopentyloxy group, which disrupts plant membranes. In terms of insecticidal activity, the hexyloxy group contributes to high mortality by interacting with insect cell membranes.
Insecticidal activity
The potential insecticidal properties of the novel quaternary pyridinium salts were meticulously evaluated against C. maculatus pests. In preliminary screening assays, which were conducted at a 1% treatment concentration, all test compounds presented high mortality rates within a mere 24-h timeframe, rivaling the performance of the commercial standard BAGIRA (Table 8). Notably, 1-(2-(hexyloxy)-2-oxoethyl)pyridin-1-ium chloride was the most efficacious, achieving an impressive kill rate of 92.5%. This result suggests relatively robust insecticidal activity within the series. Predictably, pest mortality exhibited a concentration-dependent decline at lower dosage levels. Notably, both the benzyloxy and hexyloxy derivatives retained substantial pesticidal efficacy even at reduced concentrations ranging from 0.1 to 0.01%, underscoring their versatility within an effective dose range. This preliminary assessment underscores the potential of these novel quaternary pyridinium compounds as promising candidates for natural insect control agents. It is evident that their toxicological impact is contingent upon both the concentration and the specific oxyalkyl substituents employed, thereby providing invaluable guidance for forthcoming lead optimization endeavors. Consequently, further targeted investigations are warranted to validate their utility as biodegradable alternatives for insect control. Quaternary pyridinium salts, characterized by their cationic nitrogen moieties, facilitate interactions with insect cell membranes and organelles. Although the presence of lipophilic oxyalkyl domains typically serves to enhance cuticle penetration and partitioning, the inclusion of polar ester groups within the hydrocarbon chains of tertiary ammonium salts is known to impede their penetration through biological membranes. The incorporation of more branched and shorter chains, exemplified by isopentyloxy, imparts heightened lipophilicity, potentially resulting in nonspecific membrane disruption. Conversely, longer linear chains, as observed in hexyloxy derivatives, and the introduction of aromatic groups, such as benzyloxy, may result in selectivity in targeting ion channels and receptors. This lends credence to the likelihood of multiple toxicity mechanisms, encompassing both membrane disruption and receptor-mediated effects. The realization that structural optimization could yield compounds tailored to target essential physiological systems further underscores the potential of these compounds as natural pesticides. The structure–activity data gleaned from this investigation provide key insights into the intricate mechanisms underpinning membrane and target-based insecticidal activity, thereby serving as a compass to navigate future analog design efforts in the realm of natural pesticide development.
Computational analysis
Density functional analysis
The calculated reactivity descriptors of the three molecules are presented in Table 9. The optimized geometries, directions of the dipole moments, frontier molecular orbitals, and distributions of the electrostatic potential are shown in detail in Figs. 2, 3, and 4. The HOMO molecular orbitals are localized on the ligands, whereas the LUMO orbitals are localized mainly on the C5N rings. Therefore, all three molecules are characterized by almost the same LUMO energies, and the difference in their electronic properties is determined by the HOMO. HOMO energies slightly increase in a series of molecules: 1-(2-(isopentyloxy)-2-oxoethyl)pyridin-1-ium, 1-(2-(hexyloxy)-2-oxoethyl)pyridin-1-ium, and 1-(2-(benzyloxy)-2-oxoethyl)pyridin-1-ium. This growth is accompanied by a decrease in chemical rigidity and stability. However, the values of all the quantum descriptors for all three molecules are almost the same. Figure 5 shows the total and partial densities of the electronic states of the three molecules. One can see that carbon atoms provide major contributions to both frontier orbitals of each molecule.
Structure (a), HOMO (b), and LUMO (c) frontier orbitals and electrostatic potential (d) of 1-(2-(benzyloxy)-2-oxoethyl)pyridin-1-ium. The blue arrow indicates the direction of the dipole moment. Brown, white, blue, and red balls represent carbon, hydrogen, nitrogen, and oxygen atoms, respectively
Total and partial densities of electronic states for 1-(2-(isopentyloxy)-2-oxoethyl)pyridin-1-ium (a), 1-(2-(hexyloxy)-2-oxoethyl)pyridin-1-ium (b), and 1-(2-(benzyloxy)-2-oxoethyl)pyridin-1-ium (c). The peaks of the density of states are broadened by Gaussians with σ = 0.2 eV
Smaller energy gaps, as observed for the benzyloxy derivative (2.94 eV), suggest greater reactivity and potential for stronger biological interactions due to greater chemical instability. Higher dipole moments indicate better interactions with polar environments, enhancing solubility and biological engagement. The hexyloxy derivative shows the highest dipole moment (13.10 Debye), suggesting effective interactions with biological media. The lower ionization potential of the benzyloxy derivative indicates the ease of oxidation, affecting its reactivity under oxidative biological conditions. The lower electronegativity and greater softness of the benzyloxy derivative imply that it is more electrophilic, facilitating interactions with biological targets. This derivative’s properties suggest that it can effectively interact with nucleophilic sites in biological molecules. These physicochemical traits imply that molecular structures with specific features, such as the benzyloxy group, enhance interactions with biological systems, which is correlated with observed bioactivities such as herbicidal and insecticidal effects.
Molecular docking analysis
For molecular docking analysis, some proteins related to different kinds of cancers were chosen. The following proteins were considered: 1JNX (relevant to breast cancer), 6V9C (relevant to liver cancer), and 1X2J (relevant to lung cancer). The structures of these proteins and the docking sites for the selected compounds are shown in Figs. 6, 7, and 8, respectively. The values of VS and Ka are listed in Table 10. All three molecules dock to the same cavities on the proteins (the only exception is the docking of 1-(2-(hexyloxy)-2-oxoethyl)pyridin-1-ium on 1JNX). 1-(2-(Benzyloxy)-2-oxoethyl)pyridin-1-ium, which contains two hexagonal rings, has the highest negative value of VS. Therefore, this molecule is the most biologically active. According to Table 10, 1-(2-(benzyloxy)-2-oxoethyl)pyridin-1-ium docks more strongly to 1X2J than to the other proteins under consideration.
The best docking site for 1-(2-(isopentyloxy)-2-oxoethyl)pyridin-1-ium attached to the 1JNX (a), 6V9C (b), and 1X2J (c) proteins. A general view (left) and a detailed view of the interacting region (right) are both presented for each protein. The blue arrows indicate the docking molecules
The best docking site for 1-(2-(hexyloxy)-2-oxoethyl)pyridin-1-ium attached to the 1JNX (a), 6V9C (b), and 1X2J (c) proteins. A general view (left) and a detailed view of the interacting region (right) are both presented for each protein. The blue arrows indicate the docking molecules
The best docking site for 1-(2-(benzyloxy)-2-oxoethyl)pyridin-1-ium attached to the 1JNX (a), 6V9C (b), and 1X2J (c) proteins. A general view (left) and a detailed view of the interacting region (right) are both presented for each protein. The blue arrows indicate the docking molecules
Petra/Osiris/Molinspiration (POM) analysis
Petra analysis provides predictions of some physical and chemical properties of organic molecules, including bond dissociation enthalpies (BDEs) and free energies (BDFEs). However, novel approaches that are based on machine learning (ML) have higher accuracies for these values. This is why one such modern ML technique was applied to estimate the BDE and BDFE of the considered molecules. The results are presented in Table 11. According to the data obtained, the C‒N bonds are the weakest in all three molecules. The BDE and BDFE values corresponding to these bonds are almost the same and equal to 60 and 47 kcal/mol, respectively. Therefore, the molecules are quite stable and do not dissociate under normal conditions.
Osiris analysis was performed with the OSIRIS Property Explorer. The obtained data are presented in Table 12. The cLogP value shows the logarithm of the ratio of the solubilities of the selected molecules in n-octanol and water. Lower values of cLogP correspond to greater hydrophilicity. All the considered molecules have cLogP < 5; therefore, their adsorption and permeability characteristics should be considered acceptable. The logS characteristic is the logarithm of the aqueous solubility of a molecule expressed in mol/L units. Most drugs possess logS > − 4; all three molecules also satisfy this condition. The value of DL is a measure of the similarity between the considered molecule and commonly known drugs. Fragments, which are typical for drugs, identified in the considered molecules as well as their contributions to DL values are shown in Fig. 9. Only 1-(2-(Isopentyloxy)-2-oxoethyl)pyridin-1-ium has a positive DL value. Therefore, this molecule is more similar to drugs than to nondrug chemical compounds. Toxicity risks were evaluated via the empirical methods implied in the OSIRIS Property Explorer (see Table 12). The values of the drug score (DS) were calculated on the basis of all the parameters mentioned above. Molecule 3 is the safest and has the highest value of DS = 0.47.
Drug-like fragments of the considered molecules 1-(2-(isopentyloxy)-2-oxoethyl)pyridin-1-ium (a), 1-(2-(hexyloxy)-2-oxoethyl)pyridin-1-ium (b), and 1-(2-(benzyloxy)-2-oxoethyl)pyridin-1-ium (c) as well as their contributions to the corresponding DL values relevant to OSIRIS analysis
Molinspiration analysis revealed the activity of the considered molecules to common human receptors, such as GPCRs, ion channels, kinases, nuclear receptors, proteases, and enzymes. The Molinspiration scores calculated with the software are presented in Table 13. The molecules demonstrate very different bioactivities against different human receptors (see Table 13).
Estimated application
Synthesized pyridinium salts have potential for various applications across multiple fields. In agriculture, the benzyloxy derivative has promising growth-promoting properties and could be developed as a natural plant growth regulator or biofertilizer. The strong herbicidal activity of the isopentyloxy derivative suggests that it could be used as a selective biopesticide for organic farming. In pharmaceuticals, the docking results indicate that these salts, especially the benzyloxy derivative, may serve as leads for developing anticancer agents that target diseases such as breast, liver, and lung cancers. The insecticidal activity of the hexyloxy derivative highlights its potential as a biodegradable pesticide for pest control in agriculture and households. Further optimization of these compounds could lead to sustainable alternatives to conventional chemicals in agriculture, pharmaceuticals, and pest management.
Comparison analysis
The present study demonstrates the synthesis, characterization, and biological activity evaluation of novel pyridinium-based ionic liquids (ILs), offering a broader scope than similar works in the literature. For example, while a study on pyridinium ILs and maize seedlings focused on phytotoxicity and gene expression, this work explored the relationship between alkyl chain length and biological activity, extending its applications to herbicidal and insecticidal effects (Table 14). Similarly, research on pyridinium ILs for VEGFR-2 kinase inhibition has targeted cancer therapy, whereas the present study not only investigated cancer-related protein binding via molecular docking but also explored growth-promoting and pest control applications in agriculture. This highlights the versatility of the synthesized compounds. Unlike a study in which CO2 solubility was predicted via computational methods, this research applies DFT and molecular docking to explore biological activity, revealing the adaptability of these tools across various fields. While the study of the cytotoxicity in cancer cells is the focus of another study on ILs, the present work integrates cancer bioactivity with herbicidal and insecticidal properties, expanding the potential utility of pyridinium ILs in both medical and agricultural fields. Furthermore, in contrast to studies on biocompatibility for medical applications or enzyme inhibition using quercetin derivatives, this research employs docking and DFT not only for cancer-related bioactivity but also for agricultural uses such as herbicide development. By integrating experimental and computational techniques, the present work offers a comprehensive exploration of pyridinium ILs’ bioactivity, positioning them as versatile agents with potential across pharmaceutical, agricultural, and environmental domains, surpassing the narrower focus of previous studies.
Conclusion
This study achieved its objectives by successfully synthesizing and characterizing three novel pyridinium ionic liquids with high yields (up to 86%) under optimized reaction conditions. The benzyloxy derivative demonstrated the strongest plant growth-promoting effects, whereas the isopentyloxy compound exhibited potent herbicidal activity by inhibiting root and shoot growth. All synthesized compounds displayed significant insecticidal activity. Computational studies, including DFT calculations and molecular docking, provided insights into the electronic properties, reactivity, and favorable binding interactions with cancer protein targets. The benzyloxy ionic liquid emerged as the most active lead compound. The study established a clear structure‒activity relationship (SAR), where shorter, more lipophilic chains led to stronger herbicidal activity, and longer, less lipophilic chains with aromatic groups enhanced selective biological interactions. The integration of experimental and computational methods provided a comprehensive understanding of the mechanisms, supporting the rational design of optimized compounds. These findings support further targeted syntheses focused on developing sustainable bioactive agents for agricultural and pharmaceutical applications.
Data availability
No datasets were generated or analysed during the current study.
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We would like to acknowledge that large sections of this manuscript have appeared on a preprint server (Research Square and https://doi.org/10.21203/rs.3.rs-3398070/v1). The preprint version of this manuscript can be accessed at https://doi.org/10.21203/rs.3.rs-3398070/v1.
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Bakhtiyor Borikhonov: Conceptualization, Writing – Original Draft Preparation, Data Curation. Elyor Berdimurodov: Methodology, Formal Analysis, Supervision, Writing – Review & Editing. Tursunali Kholikov: Investigation, Data Analysis, Validation. W.B. Wan Nik: Resources, Data Interpretation, Project Administration. Konstantin P. Katin: Software, Computational Studies, Visualization. Muslum DEMİR: Experimental Design, Resources, Writing – Review & Editing. Frunza Sapaev: Validation, Investigation, Formal Analysis. Sherzod Turaev: Data Curation, Software, Visualization. Nigora Jurakulova: Writing – Original Draft Preparation, Investigation, Resources. Ilyos Eliboev: Supervision, Project Administration, Funding Acquisition.
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Borikhonov, B., Berdimurodov, E., Kholikov, T. et al. Development of new sustainable pyridinium ionic liquids: From reactivity studies to mechanism-based activity predictions. J Mol Model 30, 359 (2024). https://doi.org/10.1007/s00894-024-06157-y
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DOI: https://doi.org/10.1007/s00894-024-06157-y