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. 2022 Jul 8;7(28):24838–24850. doi: 10.1021/acsomega.2c03047

Substituent-Controlled Structural, Supramolecular, and Cytotoxic Properties of a Series of 2-Styryl-8-nitro and 2-Styryl-8-hydroxy Quinolines

Suman Sehlangia †, Namyashree Nayak †, Neha Garg ‡,*, Chullikkattil P Pradeep †,*
PMCID: PMC9301718  PMID: 35874236

Abstract

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Styryl quinolines are biologically active compounds with properties largely depending on the substituents on the styryl and quinoline rings. The supramolecular aspects of this class of compounds are rarely explored. In this study, two new series of styryl quinoline derivatives, bearing −OH and −NO2 groups at the eighthposition of the quinoline ring and −SCH3, −OCH3, and −Br groups on the styryl ring, have been developed, and their structural, supramolecular, and cytotoxic properties have been analyzed. Crystallographic analyses revealed the exciting substituent-dependent structural and supramolecular features of these compounds. In general, the 8 −OH substituted derivatives (SA series) exhibited a non-planar molecular geometry having larger dihedral angles (5.75–59.3°) between the planes of the aromatic rings. At the same time, the 8 −NO2 substituted derivatives (SB series) exhibited a more or less planar molecular geometry, as revealed by the smaller dihedral angles (1.32–3.45°) between the aromatic rings. Multiple O–H···O, C–H···O, O–H···N, and π–π stacking interactions among the molecules lead to fascinating supramolecular architectures such as hydrogen-bonded triple helices, zig-zag 1D chains, π–π stacked infinite chains, and so forth in their crystal lattice. Hirshfeld surface analyses confirmed the existence of strong π–π stacking and other weak bonding interactions in these compounds. The preliminary cytotoxic properties of SA and SB series compounds were evaluated against the human cervical cancer cell lines (HeLa cells), which further highlighted the roles of functional substituents on the aromatic rings. The SA series compounds with the −OH substituent on the quinoline ring exhibited better cytotoxicity than the SB series compounds with a −NO2 substituent. Similarly, the electron-withdrawing group −Br on the styryl ring enhanced the cytotoxicity in both series. The IC50 values were 2.52–4.69 and 2.897–10.37 μM, respectively, for the SA and SB series compounds. Compound S3A having −OH and −Br groups on the quinoline and styryl ring, respectively, exhibited the best IC50 value of 2.52 μM among all the compounds tested. These findings confirm the relevance of the hydroxyl group in the eighth position of quinoline. In short, the present study attempts to provide a systematic analysis of the effects of aromatic ring substituents on the structural, supramolecular, and cytotoxic properties of styryl quinolines for the first time.

1. Introduction

8-Hydroxyquinolines (8-HQs) belong to the quinoline family of heterocycles and are known for their pharmacological, optical, and analytical applications. The core structure of 8-HQs, consisting of fused pyridine and phenol rings, is considered a privileged structure for developing novel drug molecules and materials.1,2 The synthetic versatility of 8-HQs allows the generation of targeted derivatives with fine-tuned properties for a broad spectrum of applications. The interlinking of the 8-HQs with a phenyl ring through an unsaturated ethylene linker leads to 2-styryl-8-hydroxyquinolines (2S-8HQs), a highly useful derivative of 8-HQs. Such interlinking helps extend the π-conjugation of 8-HQs, enhancing the molecule’s overall electron mobility, thermal stability, and lipophilicity. As a result, the 2S-8HQs exhibit improved photophysical, conductive, and biological properties compared to simple 8-HQs.3−10 By introducing suitable functional substituents on the styryl and quinoline rings, the properties of 2S-8HQs can be improved. 2S-8HQs exhibit important pharmacological activities, including anticancer, anti-HIV-1, antimicrobial, antimalarial, and anti-Alzheimer activities.11−21 In addition, the 2S-8HQs are also explored as organic semiconductors,22−24 thermo and electrochromic materials,25 and organic light-emitting diode (OLED) materials.22,23,26−28 Still, compared to many other derivatives of 8-HQs, 2S-8HQs are a relatively less explored class of compounds, and there is an ongoing interest in developing structurally diversified 2S-8HQs for varied applications.

The principles of supramolecular chemistry are extensively used in engineering materials for therapeutic, optical, and other diverse applications.29−32 A single non-covalent interaction may be weak, but a collection of many such interactions can lead to materials with properties resembling the covalently bonded materials. The rational design of molecular systems incorporating structural motifs exhibiting specific and directional molecular recognition properties is vital in developing new materials across disciplines. For example, face-to-face π–π stacking interactions are beneficial for organic semiconductor applications.33 Similarly, planar rigid structures with extended conjugation are vital for OLED applications.34 Most importantly, supramolecular interactions play significant roles in many biological systems and drug molecules. Establishing quinoline derivatives as reliable tectons in supramolecular chemistry is important in this context. However, quinoline is a less explored structural motif in supramolecular chemistry despite its ability to exhibit strong C–H···π and π–π stacking interactions.3,26,35,36 The available reports in this direction are mainly on the metal complexes of quinoline derivatives. For example, multinuclear metal complexes,33,37 coordination polymers,38,39 and metal–organic frameworks40 have been reported using 2S-8HQ derivatives as versatile ligands. In these compounds, the 2S-8HQ ligands exhibit multiple weak bonding interactions, including C–H···O, O–H···O, C–H···π, and π–π stacking interactions, leading to supramolecular architectures such as helices, 3D frameworks, and coordination networks.10,41−44 These studies show that the supramolecular features of 2S-8HQ-based complexes can be tuned by varying the substituents on the styryl or quinoline rings.

A clear understanding of the structural and supramolecular properties of quinoline derivatives, especially styryl-quinoline derivatives, may help design novel materials for diverse applications. However, only a few structural reports on 2S-8HQs are available,45,46 and the detailed supramolecular analyses, including Hirshfeld surface analyses,47,48 are rarely reported for this class of compounds. Moreover, structural studies on the 8 −NO2 analogues of 2S-8HQs are unprecedented. In this paper, a new series of 2S-8HQs (S1A–S3A, SA series) and the corresponding 8 −NO2 analogues 2-styryl-8-nitro quinolines (2S-8NQs) (S1B–S3B, SB series) have been developed, and their detailed structural and supramolecular analyses, including Hirshfeld surface analyses, are being reported for the first time, see Scheme 1. Furthermore, preliminary studies on the cytotoxic properties of these new compounds are reported herein. The effects of different substituents on these compounds’ structural, supramolecular, and cytotoxic properties have been analyzed.

Scheme 1. General Scheme Showing the Synthesis and Chemical Structure of SA and SB Series Compounds Explored in This Study.

Scheme 1

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2. Results and Discussion

2.1. Design and Synthesis of SA and SB Series Compounds

The SA and SB series compounds were synthesized by reacting the commercially available quinaldines, 2-methyl quinoline-8-ol, and 2-methyl-8-nitroquinoline, respectively, with substituted aldehydes in acetic anhydride, as shown in Scheme 1. The aldehyde derivatives E2 and E3 are available commercially, whereas E1 was synthesized following a reported procedure.49 The condensation of quinaldines with the aldehydes yielded the acetylated styryl quinolines F1–F6. The acetyl derivatives were hydrolyzed in the presence of K2CO3 and neutralized with HCl to give the final products S1A–S3A and S1B–S3B.50 Standard analytical and spectroscopic techniques confirmed the reaction products; see Figures S1–S39 Supporting Information. S1A–S3A and S1B–S3B exhibited 1H NMR peaks in the range 7.09–8.37 ppm with J values 15.08–16.45 ppm, confirming the presence of trans vinylene groups.46,50,51 The characteristic 1H NMR peaks due to the hydroxyl groups appeared at 9.57–10.60 ppm. Single-crystal X-ray diffraction analyses were performed for the final characterization of these compounds. Suitable single crystals of these compounds were grown from the methanol/dichloromethane solvent mixture by slow evaporation.

2.2. Structural Analyses of the SA Series Compounds

The structure refinement data of S1A–S3A are given in Table S1 (Supporting Information), and the molecular structures showing the atom labeling scheme are presented in Figures 1a,b and 3a, respectively. These compounds crystallized in the monoclinic P21/n space group with a single molecule in the asymmetric unit. The crystal structure analyses confirmed that these compounds show E conformation about the styryl C=C bond. S1A and S2A exhibited a non-planar, twisted molecular geometry evident from their dihedral angles of 59.3 and 47.07°, respectively, between the planes of the quinoline and styryl rings. In comparison, S3A showed a planar geometry with a smaller dihedral angle of 5.75° between the planes of the quinoline and styryl rings. S1A–S3A exhibited typical styryl alkenyl bond lengths of 1.320(3), 1.328(4), and 1.322(4) Å, respectively.3

Figure 1.

Figure 1

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Molecular structures of (a) S1A and (b) S2A showing the atom labeling scheme; thermal ellipsoids are shown at the 50% probability level.

Figure 3.

Figure 3

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(a) Molecular structure of S3A showing atom labeling scheme. Thermal ellipsoids are shown at the 50% probability level; (b) the strong O–H···O intermolecular hydrogen bonding interactions (O2–H2···O2) between the phenolic −OH groups proceed in a 1D chain fashion. H-bonding/weak-bonding interactions are shown in turquoise, and hanging contacts are shown in pink.

The crystallographic analyses revealed that S1A and S2A exhibit similar supramolecular features. Both these compounds show two prominent O–H···O intermolecular interactions (O1–H1···O2 and O2–H2···O1) between the −OH groups on the quinoline and styryl moieties of adjacent molecules; see Table S3, Supporting Information for details. These interactions proceed in a helical fashion along the crystallographic b axis, as shown in Figures 2a and S40a. In the crystal lattice of S1A and S2A, three such supramolecular helices are arranged concentrically along the b axis, Figures 2b and S40b. As there are three concentric helices along the b axis, the unit cell parameter b is one-third of the pitch of the helical chains, that is, 5.1317(2) Å. Each helical chain is connected to the other two helical chains through two O–H···O interactions. The quinoline phenolic oxygen O1 acts as the H-bond donor in one of these interactions, while the styryl phenolic oxygen O2 acts as the acceptor in the other. The arrangement of the helical chains in a concentric fashion is supported by π–π stacking interactions between the quinoline rings; see Table S4 and Scheme S1 in the Supporting Information for details. Here, we have considered only strong π–π stacking interactions that are characterized by short centroid–centroid distances (∼3.8 Å), near-parallel ring planes (α < 10 to ∼0°), and small slip angles (β, γ < 25°) and vertical displacements (slippage < 1.5 Å). In these interactions, the quinoline moieties of adjacent molecules are stacked in an offset fashion such that the pyridine ring of one molecule is on top of the phenyl ring of the second. In the case of S1A, the perpendicular distance between the rings is in the range 3.57–3.62 Å, and the dihedral angles between the planes of the rings, that is, α, is 2.34° with a slip angle β (formed by centroid–centroid vector and the ring normal) of 18.3–20.5°. However, in S2A, the perpendicular distance between the rings is comparatively shorter, that is, 3.46–3.49 Å, with several C–C distances around 3.6 Å. The rings are almost parallel (dihedral angle between the planes α = 1.59°) in an offset arrangement with a slip angle β of 17.6–18.8°.

Figure 2.

Figure 2

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(a) Depiction of various H-bonding interactions exhibited by S1A; (b) the formation of supramolecular H-bonded helices in the crystal lattice of S1A; (c) the left- and right-handed triple helices are arranged in a rare “ridges-in-groves” fashion in the crystal lattice of S1A. H-bonding interactions are shown in turquoise, and hanging contacts are shown in pink.

S1A and S2A crystallized in a centrosymmetric space group with the molecules arranged in a centrosymmetric fashion in the unit cell. Furthermore, the crystal lattice contains pairs of opposite-handed triple-helical chains, as shown in Figures 2c and S40c. Interestingly, it can be seen that these left- and right-handed triple helices are arranged in a rare “ridges-in-groves” fashion in these molecules. This packing mode of opposite-handed triple helices allows for tighter packing and greater intermolecular contacts.51 Triple helical systems are extremely important in supramolecular chemistry because of their relevance to biological systems such as DNA.52−56 It was proposed that the triple helices represent the addition of an extra DNA strand to the double-helical structure. Triple helical systems have been actively pursued in recent years because of their significance in medicinal chemistry. We assume that the twisted molecular geometry of S1A and S2A and their strong supramolecular interactions play vital roles in forming the supramolecular helices in the crystal lattice.

Meanwhile, the crystal packing of S3A is dominated by intermolecular O–H···O and C–H···O interactions; see Table S3 in the Supporting Information for details. The O–H···O interactions (O2–H2···O2) between the styryl phenolic −OH groups extend in a zig-zag 1D chainlike fashion along the b axis, see Figure 3b. A weak C–H···O interaction (C14–H14···O1) involving a styryl ring carbon (C14) and the −OH group on the quinoline ring also supports the zig-zag 1D chains.

Comparing the structural features of S1A–S3A, it is noted that the molecules S1A and S2A have a twisted, non-planar geometry, while S3A has a planar geometry. S1A and S2A possess −SCH3 and −OCH3 groups, respectively, on the styryl ring, while S3A bears a −Br unit. It can be noted that the introduction of an electron-withdrawing group (EWG) such as −Br on the styryl phenolic ring makes the molecule more planar compared to the twisted molecular structure exhibited by S1A and S2A, having electron-donating groups (EDGs) −SCH3 or −OCH3. The difference in the molecular structure, in turn, affects the supramolecular structures as well. The absence of a twisted molecular geometry in S3A leads to a zig-zag chainlike arrangement instead of a helical structure. Another observation is that S1A and S2A exhibit aromatic π–π stacking interaction among molecules, while S3A does not show such interactions. These observations suggest that the nature of the substituents on the styryl ring affects the structural and supramolecular features of 2S-8HQ derivatives.

2.3. Structural Analyses of the SB Series Compounds

Among the SB series compounds having a −NO2 substituent at the eighth position of the quinoline ring, S1B and S2B crystallized in the orthorhombic Pbca space group, while S3B crystallized in the monoclinic P21/c space group. The asymmetric unit contains one molecule of the compound and a solvent water molecule in all these cases. S1B–S3B showed E conformation about the styryl C=C bond; see Figures 4a, 6a, and 8a. The crystallographic data of S1B–S3B are given in Table S2 in the Supporting Information. One important observation about the structural features of SB series compounds is that they exhibit a planar molecular geometry compared to the SA series compounds. This is evident from the dihedral angles of 1.32–3.45° shown by the SB series compounds between the planes of the aromatic rings. SB series compounds also exhibited typical styryl alkenyl bond distances in the range of 1.298(5)–1.326(4) Å.

Figure 4.

Figure 4

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(a) Molecular structure of S1B showing atom labeling scheme. Thermal ellipsoids are shown at the 50% probability level; (b) strong π–π stacking interactions between adjacent molecules of S1B (green dotted lines) lead to forming π stacked dimers. Hanging contacts are shown in pink.

Figure 6.

Figure 6

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(a) Molecular structure of S2B showing the atom labeling scheme. Thermal ellipsoids are shown at a 50% probability level; (b) strong π–π stacking interactions between adjacent molecules of S2B (green dotted lines) lead to the formation of π stacked dimers.

Figure 8.

Figure 8

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(a) Molecular structure of S3B showing the atom labeling scheme. Thermal ellipsoids are shown at a 50% probability level; (b) the O3···O4 and N1···O4 interactions (turquoise dotted lines) and the π–π stacking interactions (green dotted lines) lead to stacked dimers in S3B. Hanging contacts are shown in pink.

The molecular structure of S1B showing the atom labeling scheme is given in Figure 4a. In the crystal lattice of S1B, strong π–π stacking interactions between the adjacent molecules lead to the formation of π-stacked dimers, as shown in Figure 4b. In these dimers, the molecules are stacked head-to-tail, that is, the styryl phenol ring of one molecule interacts with the quinoline ring of the other and vice versa. The centroid-to-centroid distances are 3.59–3.73 Å, and the perpendicular distances between the rings are 3.42–3.49 Å in these dimers.

In the crystal lattice, such π-stacked dimers undergo further π–π stacking interactions leading to infinite chains, see Figure 5a. In this inter-dimer stacking, the quinoline rings of the adjacent dimers interact because of which the stacking proceeds in an offset/stepped fashion. The adjacent π-stacked chains are arranged in a zig-zag fashion in the crystal lattice, see Figure 5b. The π-stacked chains are further interlinked into the 3D network structure by several O–H···O and N–H···O intermolecular interactions exhibited by S1B molecules, as shown in Figure 5b. The details of the H-bonding interactions are listed in Table S5 in the Supporting Information, and the details of the π–π stacking interactions are listed in Table S6 in the Supporting Information.

Figure 5.

Figure 5

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(a) π-Stacked dimers undergo further π–π stacking interactions (turquoise dotted lines) with other dimers in a stepped fashion leading to infinite chains in the crystal lattice of S1B; (b) the adjacent π-stacked chains are arranged in a zig-zag fashion in the crystal lattice. These chains are further interconnected through various H-bonding/weak bonding interactions (turquoise dotted lines) into a 3D network structure. The hanging contacts are shown in pink.

S2B also shows supramolecular interactions quite similar to S1B. Solid π–π stacking interactions between adjacent molecules of S2B lead to π-stacked dimers, as shown in Figure 6b. The molecules are arranged in a head-to-tail fashion (styryl to quinoline ring distance 3.622 Å) in these dimers, which undergo further π–π stacking interactions with adjacent dimers in a stepped fashion forming infinite chains, see Figure 7a. The π-stacked chains are further inter-connected through various hydrogen/weak bonding interactions (C18–H18···O3, C7–H7···O4, and O3–H3···O5, see Figure 6b), leading to a highly hydrogen-bonded 3D network of π–π stacked dimers in the crystal lattice, Figure 7b.

Figure 7.

Figure 7

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(a) π-Stacked dimers undergo further stacking interactions (turquoise dotted lines) in an offset fashion in S2B, leading to infinite chains; (b) the π-stacked chains are further inter-connected through various hydrogen/weak bonding interactions (turquoise dotted lines), leading to a highly hydrogen-bonded 3D network in the crystal lattice. The hanging contacts are shown in pink.

In the crystal lattice of S3B, hydrogen bonding interactions exist between the styryl phenolic −OH and the quinoline N with the solvent water molecules (O3···O4 interaction and N1···O4 interaction), as shown in Figure 8b. There are also π–π stacking interactions between the adjacent molecules leading to chains, see Figure 9a. In these interactions, the centroid-to-centroid distances between the styryl rings are 3.872 Å, while the similar distances between the quinolyl rings are 3.742 Å. Unlike in S1B and S2B, these π–π stacking interactions are not in a head-to-tail fashion. Another difference here is that the π–π stacking interactions are not in a stepped fashion as observed in S1B and S2B. Intermolecular connections among the π-stacked chains through C2···O2 and N1···O4 interactions lead to a layered packing arrangement in the crystal lattice, see Figure 9b.

Figure 9.

Figure 9

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(a) π-Stacked dimers undergo further stacking interactions (turquoise dotted lines) in S3B, leading to chains; (b) the π–π stacked chains are interconnected in a layered fashion through various H-bonding interactions (turquoise dotted lines). Hanging contacts are shown in pink.

2.4. Hirshfeld Surface Analyses

Hirshfeld surface analyses were performed to get a qualitative and quantitative understanding of the inter- and intra-molecular interactions in SA and SB series compounds.57,58 A Hirshfeld surface can be mapped over dnorm (dnormalized), shape index, and curvedness, each providing different pieces of information about the interatomic interactions and crystal packing. The dnorm is a contact distance parameter that combines de (distance from the point to the nearest nucleus external to the surface), and di (distance to the nearest nucleus internal to the surface), and each is normalized by the van der Waals (vdW) radii of the atoms involved in the close contact. The Hirshfeld surface mapped over dnorm has different colors such as red, white, and blue. The red spot indicates interatomic interactions smaller than the sum of the vdW radii of the atoms involved in the contacts. In contrast, the white and blue spots correspond to the interatomic distances equal to or greater than the vdW radii of the atoms involved in the contacts.59 The curvedness maps help to identify planar stacking interactions as relatively large green flat regions on such surfaces indicate the possibility of stacking interactions. The Hirshfeld surface mapped over the shape-index provides information regarding minute changes in the surface shape and highlights the regions where the two molecular Hirshfeld surfaces touch each other. The shape index maps use a red and blue color scheme for complementary pairs of hollows and bumps.

The Hirshfeld surfaces calculated for S1A–S3A and S1B–S3B are given in Figures 10 and 11. Different types of short-range interactions present in the crystal structure of these molecules can be seen on the Hirshfeld surface mapped over dnorm as red spots, see Figure 12. The most crucial feature here is the Hirshfeld surfaces that are simultaneously flat green on the curvedness maps and are patterned by red and blue triangles touching each other on the shape index maps, see Figures 10b and 11b. Such patterns indicate the presence of π–π stacking between adjacent molecules. It can be noted that such patterns are visible in most of these molecules, suggesting the existence of π–π stacking interactions as observed earlier by the crystal structure analyses.

Figure 10.

Figure 10

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Hirshfeld surfaces mapped over (a) dnorm; (b) shape-index; and (c) curvedness of S1A–S3A.

Figure 11.

Figure 11

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Hirshfeld surfaces mapped over (a) dnorm; (b) shape-index; and (c) curvedness of S1B–S3B.

Figure 12.

Figure 12

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The short-range C–H···O interaction in (a) S1A; (b) S2A; and (c) S3A, respectively.

The relative contributions of various intermolecular interactions to the Hirshfeld surface areas of S1A–S3A and S1B–S3B were calculated by analyzing the 2D fingerprint plots, as shown in Figures 13 and S41. These plots depict the percentage contribution of each type of contact to the total Hirshfeld surface area. As shown, the significant contributions to the Hirshfeld surfaces come from H···H, C···H, and O···H interactions in all the cases with varying percentages. Another significant contribution is from C···C interactions. In the case of SA series compounds, the C···C interactions were in the range 6.8–8.8. However, in the case of SB series compounds, the relative contribution of C···C interactions was comparatively high, that is, 8.9–11.8. These interactions further highlight the existence of π–π stacking interactions in these molecules and suggest that such interactions are more prominent in SB series compounds, probably due to their comparatively more planar molecular geometry.

Figure 13.

Figure 13

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2D fingerprint plot of S1A–S3A shows different types of interactions involved with their respective contribution.

2.5. Cytotoxicity Study

Studies on the cytotoxicity aspects of the SA and SB series compounds were conducted on human cervical carcinoma cell lines (HeLa cells) using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) assay. 5 × 103 cells per well were plated and, after 24 h of incubation, treated with the dimethyl sulfoxide (DMSO) solubilized compounds S1A–S3A, and S1B–S3B, with a time frame of 48 h in a dose-dependent manner (0.5–50 μg/mL). The results summarized in Figures 14 and 15 and Table 1 show that most of the target compounds exhibited appreciable cytotoxicity against the HeLa cells.

Figure 14.

Figure 14

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Cytotoxicity assay. S1A–S3A are incubated in HeLa cells for 48 h in a dosage-dependent manner.

Figure 15.

Figure 15

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Cytotoxicity assay. S1B–S3B are incubated in HeLa cells for 48 h in a dosage-dependent manner.

Table 1. IC50 and IC90 Values of SA and SB Series Compounds against HeLa Cells.

styryl derivate compound IC50 (μM) IC90 (μM)
S1A 4.694 30.066
S2A 3.859 44.342
S3A 2.518 36.694
S1B 10.370 75.439
S2B 7.653 52.975
S3B 2.897 83.222
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The results of the cytotoxicity studies on the SA series compounds are presented in Figure 14. These compounds exhibited IC50 values in the 2.52–4.69 μM range against the tested cell line. The compound S3A exhibited a promising IC50 value of 2.52 μM in the series. The SB series compounds exhibited IC50 values in the range of 2.897–10.370 μM, indicating a comparatively lower cell inhibition property than the SA series compounds, see Figure 15. Compound S3B showed the best IC50 value of 2.897 μM in the series. Compared to SB series compounds, the SA series compounds exhibited better cytotoxicity with IC50 values of 2.52–4.69 μM. S3A was the most cytotoxic compound exhibiting the best IC50 value (2.52 μM) among the compounds tested in this study. The vehicle control DMSO (0.2%) showed no significant difference in cell cytotoxicity.

Analyses of the results show a pronounced effect of the substituents on the quinoline and the styryl rings in determining the cytotoxicity of these compounds. The SA series compounds having −OH substituent at the eighth position of the quinoline ring exhibited comparatively better performances than the SB series compounds with a −NO2 substituent at the eighth position. Previous studies by Mrozek-Wilczkiewicz et al. on a panel of colon cancer cells (HCT 116) had also observed the importance of the hydroxyl group at the C8 position of quinoline. It was noted that the chelating properties due to the presence of the −OH group extend the activity of the styryl quinoline. While analyzing the effects of the substituents on the styryl ring, it is noted that the most active derivative (lowest IC50 value) in each series was the one bearing a −Br substituent. The derivatives bearing the −OCH3 and −SCH3 substituents on the styryl ring were less active in each series (see Table 1). This highlights the importance of an EWG halogen substituent on the styryl ring in determining the cytotoxicity of this class of compounds, as reported earlier.14 Furthermore, it is evidenced that the introduction of additional EDGs (i.e., −OCH3 and −SCH3) on the styryl ring causes a reduction in the activity.

It can also be noted that the compounds studied here (SA and SB series) exhibited comparable or better cytotoxicity than many previously reported styryl quinoline derivatives (see Table S7 in the Supporting Information for a comparison). Compared to unsubstituted styryl quinoline derivatives, a series of styryl quinolines with halogenated styryl rings demonstrated improved activity and selectivity indices.14 In the present study, we have not explored the detailed mechanistic aspects of cytotoxicity exhibited by SA and SB series compounds. However, we expect a mode of action as reported for similar styryl quinoline derivatives.11,14 The significance of the hydroxyl group at the C-8 position for anticancer action also points to metal chelation as a possible mechanism reported for similar compounds.14,60 However, more detailed mechanistic studies are required to establish the actual mode of action of the present compounds.

3. Conclusions

New series of 2S-8HQs and 2S-8NQs having different substituents on the styryl ring have been designed, synthesized, and structurally characterized. These new derivatives’ structural, supramolecular, and cytotoxicity aspects have been studied and compared. The roles of various EDGs and EWGs on the styryl ring in deciding their properties have been analyzed. The cytotoxic assay on the HeLa cervical cancer cell line showed that the hydroxy analogues exhibit better cytotoxicity than the nitro analogues. These findings confirm the relevance of the hydroxyl group in position C-8 of quinoline. An EWG on the styryl ring of the molecule is required for high cytotoxicity levels. These new derivatives may therefore help understand the complex biological effects of styryl-quinolines. This study also attempted to establish styryl-quinolines as potential supramolecular synthons, especially for π-stacked structures, for the first time.

4. Experimental Section

4.1. Materials and Instrumentation

All the chemicals were purchased from Sigma-Aldrich. Solvents used were of spectroscopic grade and were used without further treatment. 1H and 13C NMR spectra were recorded on a Jeol-JNM 500 MHz NMR spectrometer using DMSO-d6 and CDCl3 as solvents and tetramethylsilane as the internal standard. High-resolution mass spectrometry (HR-MS) data were recorded on Bruker HD compact instrument.

4.2. Single Crystal X-ray Diffraction Analysis

Single-crystal X-ray data were collected on an Agilent SuperNova diffractometer, equipped with a multilayer optics monochromated dual source (Cu and Mo) and an Eos CCD detector, using Cu Kα radiation (1.54184 Å) at room temperature. Data acquisition, reduction, and absorption correction were performed by using CrysAlisPRO.61 The structure was solved with ShelXS62 program using direct methods and refined on F2 by full-matrix least-squares techniques with ShelXL62 through the Olex2 (v.1.2) program package.63 Anisotropic displacement parameters were applied for all the atoms, except for hydrogen atoms. The hydrogen atoms were placed in calculated positions and refined as riding atoms using isotropic displacement parameters. Due to the poor crystal quality, the crystal data of S1A, S2A, and S2B displayed some B level alerts in Checkcif. Specific explanations for the B-level alerts are given in the Supporting Information.

CCDC 2170717–2170722 contains the supplementary crystallographic data for this paper. These data can be obtained free of charge from The Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_request/cifdata.

4.3. Hirshfeld Surface Analyses

To better understand and quantify the intra- and inter-molecular interactions present in the crystal structure of compounds, Hirshfeld surface analyses were performed using the Crystal explorer 17.5 program.64 The Hirshfeld surfaces were drawn from the .cif files of the compounds, with a normalized contact distance (dnorm), which can be expressed as a combination of internal di, external de, and vdW radii of the atoms as below47,48,65

4.3.

4.4. Cell Viability Assay

The in vitro cytotoxicity of styryl derivatives was evaluated by MTT assay using HeLa cell line with a cell density of 5 × 104 cells per well. Cells were cultured in Dulbecco’s modified Eagle medium (DMEM) containing 1% fetal bovine serum at 37 °C in 5% CO2 in a 96 well plate. After cell adherence, media were replaced with new DMEM containing DMSO solubilized styryl derivatives in quadruples and incubated for 48 h. Cells without any treatment were selected as a positive control, with only media as negative control and 0.2% DMSO as vehicle control. 10% of MTT dye was added to evaluate the viability of cells. After incubation of 3 h, 100 μL of DMSO was added to each well and read at the absorbance of 570 nm with 650 nm as reference using Tecan Infinite M200 PRO plate reader.

4.4.1. Synthesis of SA and SB Series Compounds

As shown in Scheme 2, the target SA and SB series compounds were synthesized starting from 4-substituted phenol via a reported procedure.49,50

Scheme 2. Overall Synthetic Scheme of Compounds S1A–S3A and S1B–S3B.

Scheme 2

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4.4.2. General Procedure for the Synthesis of E1

These compounds were synthesized by heating the 4-(methylthio) phenols (1 mmol) with hexamethylenetetramine (1.2 mmol) in trifluoroacetic acid at 130 °C for 24 h (TLC monitoring) following a reported procedure.50 The products were purified by column chromatography using the ethyl acetate/hexane mixture.

E1 was obtained as a light-yellow solid in 45% yield. 1H NMR (500 MHz, CDCl3): δ ppm 10.82 (s, 1H), 9.77 (s, 1H), 7.40 (d, J = 4.85 Hz, 2H), 6.86 (d, J = 8.95 Hz, 1H), 2.39 (s, 3H). 13C NMR (125 MHz): δ ppm 196.2, 160.0, 137.8, 133.4, 128.6, 121.0, 118.5, 17.9. MS (HR-MS) m/z: calcd for C8H8O2S ([M – H]), 167.02; found, 167.05.

4.4.3. General Procedure for the Synthesis of F1–F6

A mixture of compound E (1 mmol), 2-methyl-8-substituted quinoline (1 mmol), and acetic anhydride was heated at 130 °C under a nitrogen atmosphere for 24 h (TLC monitoring). After that, the reaction was quenched by pouring it into an ice-water mixture with stirring. The crude compound F thus separated was filtered, dried, and purified by recrystallization from ethyl acetate following a reported procedure.49

F1 was obtained as a brownish solid in 86% yield; 1H NMR (500 MHz, CDCl3): δ ppm 8.03 (d, J = 8.95 Hz, 2H), 7.55–7.62 (m, 2H), 7.48 (d, J = 8.95 Hz, 1H), 7.34–7.40 (m, 2H), 7.22 (d, J = 15.8 Hz, 1H), 7.14–7.17 (m, 1H), 6.97 (d, J = 8.95 Hz, 1H), 2.45 (s, 6H), 2.31 (s, 3H); 13C NMR (125 MHz): δ ppm 169.8, 169.4, 155.3, 147.5, 146.6, 141.0, 136.6, 136.4, 131.6, 129.8, 128.8, 128.0, 127.7, 126.0, 125.7, 125.4, 123.4, 121.8, 120.6, 21.1, 21.0, 16.6. MS (HR-MS) m/z: calcd for C22H19O4NS ([M + H]+), 394.10; found, 394.08.

F2 was obtained as a brown solid in 87% yield; 1H NMR (500 MHz, CDCl3): δ ppm 8.02 (d, J = 8.25 Hz, 1H), 7.62 (s, 1H), 7.57 (d, J = 9.65 Hz, 1H), 7.48 (d, J = 8.25 Hz, 1H), 7.33–7.39 (m, 2H), 7.21 (d, J = 15.8 Hz, 1H), 7.17 (d, J = 2.75 Hz, 1H), 6.95 (d, J = 8.95 Hz, 1H), 6.81 (dd, J = 8.95 Hz, 1H), 3.76 (s, 3H), 2.45 (s, 3H), 2.30 (s, 3H); 13C NMR (125 MHz): δ ppm 169.8, 157.5, 155.5, 147.5, 142.6, 141.0, 136.5, 131.2, 130.0, 128.8, 128.1, 126.0, 125.7, 123.7, 121.7, 120.5, 115.5, 111.3, 55.8, 21.1, 20.0. MS (HR-MS) m/z: calcd for C22H19O5N ([M + H]+), 378.12; found, 378.12.

F3 was obtained as a dark brown solid in 88% yield; 1H NMR (500 MHz, CDCl3): δ ppm 8.13 (d, J = 8.95 Hz, 1H), 7.86 (d, J = 2.75 Hz, 1H), 7.65–7.67 (m, 1H), 7.55 (dd, J = 7.9 Hz, 1H), 7.41–7.48 (m, 3H), 7.29 (s, 1H), 7.24–7.28 (m, 1H), 6.99 (dd, J = 8.25 Hz, 1H), 2.38 (s, 3H), 2.07 (s, 3H); 13C NMR (125 MHz): δ ppm 170.0, 169.2, 155.0, 147.8, 147.6, 141.0, 136.8, 132.3, 132.2, 131.5, 130.0, 129.0, 126.8, 126.3, 125.7, 124.7, 122.0, 120.8, 119.7, 21.1, 20.7. MS (HR-MS) m/z: calcd for C21H16O4NBr ([M + H]+), 426.02; found, 426.02.

F4 was obtained as a dark brown solid in 89% yield; 1H NMR (500 MHz, CDCl3): δ ppm 8.11 (dd, J = 8.25 Hz, 1H), 7.93 (dd, J = 13.05 Hz, 2H), 7.88 (d, J = 8.25 Hz, 2H), 7.58 (d, J = 2.05 Hz, 1H), 7.51 (dd, J = 8.2 Hz, 1H), 7.43–7.46 (m, 1H), 7.17–7.20 (m, 1H), 7.00 (dd, J = 8.25 Hz, 1H), 2.46 (s, 3H), 2.41 (s, 3H); 13C NMR (125 MHz): δ ppm 169.9, 157.2, 148.2, 147.0, 139.6, 136.6, 136.5, 131.7, 129.5, 129.2, 129.1, 128.5, 128.3, 124.9, 124.7, 124.1, 123.6, 122.4, 21.0, 16.6. MS (HR-MS) m/z: calcd for C20H16O4N2S ([M + H]+), 381.08; found, 381.09.

F5 was obtained as a brown solid in 90% yield; 1H NMR (500 MHz, CDCl3): δ ppm 8.11 (d, J = 8.95 Hz, 1H), 7.88–7.94 (m, 3H), 7.53 (d, J = 8.25 Hz, 1H), 7.43–7.46 (m, 1H), 7.20 (dd, J = 15.8 Hz, 2H), 6.98 (d, J = 8.95 Hz, 1H), 6.83–6.86 (m, 1H), 3.79 (s, 3H), 2.39 (s, 3H); 13C NMR (125 MHz): δ ppm 170.2, 157.6, 157.4, 148.2, 143.1, 139.7, 136.6, 131.6, 130.1, 129.4, 129.0, 128.13, 124.7, 124.1, 123.9, 122.3, 116.2, 110.9, 55.9, 21.0. MS (HR-MS) m/z: calcd for C20H16O5N2 ([M + H]+), 365.11; found, 365.11.

F6 was obtained as a brown solid in 87% yield; 1H NMR (500 MHz, CDCl3): δ ppm 8.12 (d, J = 8.25 Hz, 1H), 7.96 (d, J = 7.6 Hz, 1H), 782–7.89 (m, 2H), 7.41–7.50 (m, 4H), 7.13 (dd, J = 16.5 Hz, 1H), 7.00 (d, J = 8.95 Hz, 1H), 2.48 (s, 3H); 13C NMR (125 MHz): δ ppm 169.5, 156.6, 148.1, 148.0, 139.4, 136.7, 132.6, 131.7, 130.7, 129.4, 129.3, 128.3, 124.8, 124.7, 124.0, 122.6, 119.46, 117.6, 20.9. MS (HR-MS) m/z: calcd for C19H13O4N2Br ([(M + 2) + H]+), 415.00; found, 414.99.

4.4.4. General Procedure for the Synthesis of S1A–S3A and S1B–S3B

To a solution of the corresponding compound F (1 mmol) in methanol was added K2CO3 (1.5 mmol), and the reaction mixture was stirred at room temperature for 120 min. After completing the reaction, as monitored by TLC, the reaction mixture was poured into water and neutralized with HCl solution, and the precipitate was filtered and dried. The crude product thus obtained was purified by recrystallization from ethanol.

S1A was obtained as a brown solid in 87% yield. 1H NMR (500 MHz, DMSO-d6): δ ppm 10.14 (s, 1H), 9.57 (s, 1H), 8.26 (d, J = 8.95 Hz, 1H), 8.09 (d, J = 16.45 Hz, 1H), 7.78 (d, J = 8.95 Hz, 1H), 7.59 (d, J = 2.75 Hz, 1H), 7.56 (s, 1H), 7.33–7.38 (m, 2H), 7.27 (d, J = 2.05 Hz, 1H), 7.09 (d, J = 16.45 Hz, 1H), 6.94 (d, J = 8.95 Hz, 1H), 2.50 (s, 3H); 13C NMR (125 MHz): δ ppm 154.6, 154.1, 153.0, 138.3, 136.4, 129.8, 129.7, 129.0, 127.9, 127.7, 126.9, 126.8, 124.0, 120.6, 117.6, 117.0, 111.3, 17.0. HRMS m/z: calcd for C18H15O2NS [M + H]+, 310.08; found, 310.07.

S2A was obtained as a light yellow solid in 85% yield. 1H NMR (500 MHz, DMSO-d6): δ ppm 9.55 (s, 1H), 8.26 (d, J = 8.95 Hz, 1H), 8.08 (d, J = 16.45 Hz, 1H), 7.78 (d, J = 8.9 Hz, 1H), 7.53 (d, J = 15.8 Hz, 1H), 7.34–7.39 (m, 2H), 7.20 (d, J = 3.45 Hz, 1H), 7.08 (dd, J = 8.9 Hz, 1H), 6.86 (d, J = 8.95 Hz, 1H), 6.78–6.80 (m, 1H), 3.75 (s, 3H); 13C NMR (125 MHz): δ ppm 154.2, 152.9, 152.3, 150.0, 138.2, 136.4, 130.0, 128.4, 127.6, 126.8, 123.4, 120.3, 117.6, 116.9, 116.1, 111.6, 116.3, 55.4. HRMS m/z: calcd for C18H15O3N [M – H], 292.10; found, 292.10.

S3A was obtained as a dark brown solid in 87% yield. 1H NMR (500 MHz, DMSO-d6): δ ppm 8.24 (d, J = 8.90 Hz, 1H), 8.08 (d, J = 16.5 Hz, 1H), 7.75 (d, J = 8.95 Hz, 1H), 7.72 (d, J = 2.75 Hz, 1H), 7.62 (d, J = 16.5 Hz, 1H), 7.32–7.38 (m, 2H), 7.24 (d, J = 8.9 Hz, 1H), 7.08 (d, J = 6.85 Hz, 1H), 6.91 (d, J = 8.25 Hz, 1H); 13C NMR (125 MHz): δ ppm 157.7, 154.2, 153.0, 138.3, 136.4, 131.7, 130.4, 129.8, 128.8, 127.6, 126.8, 125.7, 120.6, 118.8, 117.5, 111.3, 108.8. HRMS m/z: calcd for C17H12O2NBr [M + H]+, 342.00; found, 342.04.

S1B was obtained as a dark brown solid in 88% yield. 1H NMR (500 MHz, DMSO-d6): δ ppm 10.19 (s, 1H), 8.52 (d, J = 8.95 Hz, 1H), 8.22–8.24 (m, 2H), 8.04 (s, 1H), 7.97–8.00 (m, 1H), 7.64–7.69 (m, 2H), 7.52 (d, J = 16.5 Hz, 1H), 7.18 (d, J = 8.25 Hz, 1H), 6.92 (d, J = 8.25 Hz, 1H), 2.50 (s, 3H); 13C NMR (125 MHz): δ ppm 158.1, 154.6, 147.6, 138.5, 137.0, 131.7, 130.3, 127.8, 127.6, 127.23, 127.0, 125.0, 123.5, 123.4, 122.0, 116.9, 16.8. HRMS m/z: calcd for C18H14O3N2S [M – H], 337.07; found, 337.10.

S2B was obtained as a dark brown solid in 87% yield. 1H NMR (500 MHz, DMSO-d6): δ ppm 9.66 (s, 1H), 8.51 (d, J = 8.95 Hz, 1H), 8.22 (dd, J = 8.25 Hz, 2H), 8.05 (d, J = 16.5 Hz, 1H), 7.98 (d, J = 8.95 Hz, 1H), 7.67 (t, J = 7.9 Hz, 1H), 7.47 (d, J = 16.45 Hz, 1H), 7.25 (d, J = 2.72 Hz, 1H), 6.81–6.88 (m, 2H), 3.76 (s, 3H); 13C NMR (125 MHz): δ ppm 158.2, 152.3, 150.2, 147.6, 138.5, 136.9, 131.8, 131.7, 127.6, 127.2, 124.9, 123.5, 122.8, 121.8, 117.2, 111.0, 55.5. HRMS m/z: calcd for C18H14O4N2 [M + H]+, 323.10; found, 323.12.

S3B was obtained as a reddish solid in 88% yield. 1H NMR (500 MHz, DMSO-d6): δ ppm 10.60 (s, 1H), 8.52 (d, J = 8.25 Hz, 1H), 8.22 (d, J = 7.55 Hz, 2H), 7.95–7.8.00 (m, 2H), 7.86 (s, 1H), 7.65–7.68 (m, 1H), 7.53 (d, J = 15.8 Hz, 1H), 7.33 (d, J = 7.55 Hz, 1H), 6.94 (d, J = 7.55 Hz, 1H). 13C NMR (125 MHz): δ ppm 157.8, 155.5, 147.6, 138.4, 137.0, 132.5, 131.7, 130.3, 129.8, 128.4, 127.7, 125.1, 125.0, 123.6, 122.1, 118.3, 110.7. HRMS m/z: calcd for C17H11O3N2Br [M + H]+, 371.00; found, 371.03.

Acknowledgments

C.P.P. thanks SERB, Govt. of India, for financial support (project no. EMR/2016/002334) and AMRC, IIT Mandi for infrastructural facilities. S.S. thanks MHRD, Government of India, for a fellowship. N.N. acknowledges a fellowship from SERB (ECR/2017/000926). N.G. acknowledges SERB grant (ECR/2017/000926) and seed grant under IOE, Banaras Hindu University.

Supporting Information Available

The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acsomega.2c03047.

  • NMR spectra, HR-MS, crystallographic data, and additional crystallographic information (PDF)

  • Crystallographic data of S1A (CIF)

  • Crystallographic data of S1B (CIF)

  • Crystallographic data of S2A (CIF)

  • Crystallographic data of S2B (CIF)

  • Crystallographic data of S3A (CIF)

  • Crystallographic data of S3B (CIF)

Author Contributions

S.S. synthesized and characterized the compounds and wrote the draft of the paper under the supervision of C.P.P. The cytotoxic studies were performed by N.N. under the supervision of N.S. The overall project was conceived and the manuscript finalized by C.P.P.

The authors declare no competing financial interest.

Supplementary Material

ao2c03047_si_001.pdf (2.3MB, pdf)
ao2c03047_si_002.cif (188.3KB, cif)
ao2c03047_si_003.cif (251.6KB, cif)
ao2c03047_si_004.cif (174.7KB, cif)
ao2c03047_si_005.cif (253KB, cif)
ao2c03047_si_006.cif (181.1KB, cif)
ao2c03047_si_007.cif (246.2KB, cif)

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Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

ao2c03047_si_001.pdf (2.3MB, pdf)
ao2c03047_si_002.cif (188.3KB, cif)
ao2c03047_si_003.cif (251.6KB, cif)
ao2c03047_si_004.cif (174.7KB, cif)
ao2c03047_si_005.cif (253KB, cif)
ao2c03047_si_006.cif (181.1KB, cif)
ao2c03047_si_007.cif (246.2KB, cif)

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