Structural requirements for nucleophilicity and antioxidant capacity on quinoline derivatives: a theoretical study

doi:10.21203/rs.3.rs-3247130/v1

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Structural requirements for nucleophilicity and antioxidant capacity on quinoline derivatives: a theoretical study

https://doi.org/10.21203/rs.3.rs-3247130/v1

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Context

Quinoline derivatives play a crucial role in antimalarial therapy, and their biological properties are highly dependent on the basicity, particularly on the amine groups. The Amine moieties significantly contribute to the antioxidant capacity of quinoline derivatives through electron transfer mechanisms. Notably, each amine group has a distinct contribution to the antioxidant capacity, with the aliphatic amine displaying a potent electron donating capacity, the exo-aromatic amine showing an intermediate capacity, and the endo-aromatic amine demonstrating the least potent capacity. Our findings reveal a synergistic effect between the 4-amino-quinoline and tertiary amine in quinoline derivatives, enhancing their overall antioxidant capacity. However, the presence of the chlorine atom decreases its contribution as an electron withdrawing group. In comparison, chloroquine exhibits a higher antioxidant capacity than quinine, and their respective electron donation abilities are correlated with their pKa values. The synergistic effect between the 4-amino-quinoline and tertiary amine is particularly evident in chloroquine, surpassing the antioxidant capacity of 6-methoxy-4-methyl-quinoline moiety in quinine. Additionally, we have successfully proposed two new strategies for the development of chloroquine derivatives.

Methods

A theoretical study was conducted to investigate the structure-nucleophilicity and antioxidant capacity of quinoline derivatives, specifically chloroquine and quinine, through electron transfer using DFT/B3LYP/6–31 + G(d,p) methods. The HOMO values were utilized to assess nucleophilicity, while the ionization potential was indicative of electron donating capacity. To explore different aspects of the molecules, four approaches of molecular modifications were proposed: molecular fragmentation, molecular modification on amine moieties, and molecular association. These approaches aimed to provide insights into the relationships between molecular structure and nucleophilicity or antioxidant capacity. The study also involved the development of new strategies in drug design, leveraging theoretical methods to explore potential modifications and optimizations for quinoline derivatives.

quinoline derivatives

chloroquine

quinine

theoretical study

antioxidant capacity

nucleophilicity

electron-donating group

Amine compounds play a significant role on medicinal chemistry, especially due to the relationships between pharmacokinetics properties and pKa values [1]. However, understanding the individual contributions of each amine moiety in drugs containing two or more amine groups can pose challenges for researchers, even when considering the correct electronic effects. Amines are known as electron donating groups (EDGs), and their presence significantly impacts the nucleophilicity and antioxidant capacity of various molecules [2–5].

Chloroquine is a quinoline derivative with three different amine groups, originally developed as an anti-malarial drug related to quinine, it has now emerged as a significant treatment option for patients with autoimmune diseases like rheumatoid arthritis and systemic lupus erythematosus [6–8].

Several studies have investigated the potential involvement of chloroquine in autoimmune diseases, exploring numerous immunological mechanisms, such as the inhibition of antigen presentation processes, its proinflammatory effects on cytokine expression, and the inhibition of inflammasome receptors [9–12]. Recently, chloroquine and its derivatives has also been used to treat pneumonia in some countries [13–15]. Furthermore, its application in antiviral therapy has sparked interest and controversy [16]. Many of these effects can be attributed to free-radical species, which are often involved in inflammation mediated by cellular responses [17]. Consequently, antioxidant compounds are being explored as a therapeutic alternative in viral inflammation [18]. In fact, hepatic and nephrotoxicity of chloroquine in high concentration has been known and little or apparently no toxic effect at therapeutic dose by redox mechanism [19, 20].

Graves et al. have presented additional evidence supporting a potential role of oxidative stress in the action mechanism of chloroquine [21]. Moreover, a theoretical study has demonstrated the involvement of tautomerism in its redox properties [22]. Building upon these findings, our work aims to shed further light on the redox properties of chloroquine. We employ theoretical methods and a molecular modification approach to investigate the electron transfer on level of frontier orbitals (nucleophilicity) and ionization potential (antioxidant capacity).

Molecular calculations

All calculations were performed with the Gaussian 09 molecular package [23]. The geometries were optimized with the DFT/B3LYP hybrid density functional [24–27] by using the 6–31 + G(d,p) basis sets [28], and only the most stable conformations for each compound were used. The GAP values were calculated as the difference between LUMO and HOMO energies (Eq. 1). The ionization potential (IP) was calculated as the energy difference between a neutral molecule (Mol) and its respective cation free radical (Eq. 2). Usually, the single electron transfer (SET) and the hydrogen atom transfer (HAT) are the main antioxidant mechanisms [29]. SET was calculated, as shown in Eq. 3, as a difference between chloroquine (CQN) minus all other derivatives (Mol) [25].

GAP = ELUMO – EHOMO (Eq. 1)

IP = EMol•+ – EMol (Eq. 2)

SET = (ECQN•+ + EMol) – (ECQN + EMol•+) (Eq. 3)

The spin density contributions involved on resonance effect were used for a comparative study of chemical stability between the main contributions on chloroquine (1) and quinine (2) cation free-radical [30–32].

Structural approaches

In this study, four strategies have been proposed for understanding the amino impact on antioxidant capacity of chloroquine. Firstly, the molecular modifications of chloroquine (1) and quinine (10) are compared with their simplified heterocycle derivatives (3 and 4). The quinine was chosen due to its structural differences when compared to chloroquine especially due to the bioiosteric relationship between methyl and amine moiety, and regioisomeric oppositic moiety between chloro and methoxy as electron withdrawing and electron donation group. The second approach is the molecular fragmentation on chloroquine (5 and 6) and quinine (7 and 8). These proposed approaches and each compound from these three strategies are shown in Fig. 1.

In our last strategies, all modifications were only proposed on chloroquine structure (Fig. 2). Firstly, by replacement of chlorine atom (1A) and the second molecular modifications by replacement of nitrogen amine by hydrocarbon (1B-1F).

Finally, a molecular association between the better antioxidant moieties of chloroquine and quinine was proposed.

Electron donation capacity of chloroquine related to quinine

Our results demonstrated that chloroquine (1) exhibits the best antioxidant capacity through the single electron transfer mechanism (SET) when compared to quinine (2) [31, 33]. When comparing these compounds, we observed comparable HOMO values for chloroquine (-5.91 eV) and quinine (-5.77 eV), but different LUMO values (-1.53 and − 1.73 eV, respectively). According to the GAP values, quinine (4.04 eV) is more reactive than chloroquine (4.37 eV), being the most nucleophilic molecule. However, when considering the electron transfer mechanism based on their IP values, chloroquine (160.48 kcal mol^-1) has a higher electron donating capacity than quinine (162.79 kcal mol^-1) and the SET value between these compounds was 2.30 kcal mol^-1. These values are in Table 1.

Table 1

Theoretical properties of chloroquine (1), quinine (2), and simplified derivatives (3–8)
Compound	HOMO (eV)	LUMO (eV)	GAP (eV)	IP (kcal mol^-1)	SET (kcal mol^-1)
1	-5.91	-1.53	4.37	160.48	0
2	-5.77	-1.73	4.04	162.79	2.30
3	-6.21	-1.70	4.51	178.28	17.80
4	-5.97	-1.60	4.37	173.53	13.05
5	-6.76	-2.02	4.74	194.11	33.63
6	-5.86	0.02	5.88	162.78	2.29
7	-6.06	-1.68	4.38	176.55	16.06
8	-5.81	-0.13	5.67	168.53	8.05

On the contrary, the compound with the highest nucleophilicity exhibits the best antioxidant capacity in the simplified heterocycle derivatives 4-amine,7-chloro-quinoline (3) and 4-methyl,6-methoxy-quinoline (4), which are related to chloroquine and quinine. Their HOMO values were − 6.21 and − 5.97 eV and their IP values increased to 178.28 and 173.53 kcal mol^-1. According to the SET values, the difference between these componds in favor of 4-methyl,6-methoxy-quinoline (4) was 4.75 kcal mol^-1.

In addition, the same tendency was observed for the molecular fragmentation of chloroquine and quinine. The HOMO values for 7-chloro-quinoline (5) and 6-methoxy-quinoline (7) were − 6.76 and − 6.06 eV, respectively, and their IP values increased to 194.11 and 176.55 kcal mol^-1. In this case, the difference in SET values in favor of methoxy-quinoline (7) was 17.56 kcal mol^-1. In contrast, on the second moiety of molecular fragmentation we observed a significant impact of the alkylamine group (6) on chloroquine due to an expressive difference on IP values of 162.78 kcal mol^-1 when compared to alkylamine group (8) on quinine (168.53 kcal mol^-1). According to SET values, the difference between alkylamines was 5.75 kcal mol^-1 in favor of alkylamine group on chloroquine (6). In fact, quinoline ring exhibits a lower antioxidant capacity compared to the naphthalene ring or alkylamine group [32, 33]. These results align with whats is observed in other compounds known for their high electron donating capacity, such as morphine [34], folic acid [35], and dypirone [36]. Therefore, our theoretical results highlight the significant role of the aliphatic amine in chloroquine's antioxidant properties. Additionally, it is evident that the exo-aromatic amine at the 4-amine position of the quinoline ring plays a more crucial role than the endo-aromatic amine at the 1-position of the quinoline ring. This distinction can be observed through the frontier molecular orbitals (Fig. 3).

In Fig. 3 we can observe the HOMO (left) and LUMO (right) profiles for chloroquine (above) and quinine (below), which demonstrate distinct nucleophilic and electrophilic characteristics [37]. The HOMO contributions for both molecules are mainly located on the heterocycle rings, exhibiting symmetry in all groups for chloroquine, particularly on nitrogen atoms, with no contribution from the chloro moiety. On the other hand, in quinine, the most significant HOMO contribution is observed on the methoxy moiety, acting as an electron donating group. These differences significantly impact the nitrogen atom of the quinoline ring, leading to increased nucleophilicity at this position. Consequently, the results indicate that chloroquine possesses a greater nucleophilic character compared to quinine, and its π system is more effective than that of quinine. Additionally, the most prominent LUMO contributions are located in the electrophilic regions of the quinoline rings, especially between the 4-amino-quinoline system in chloroquine as compared to the 6-methoxy-quinoline in quinine.

Figure 4 displays the spin density (SD) contributions of these compounds after an electron donation. The SD contributions, indicate that all nucleophilic positions significantly impact the positive charge stabilization of chloroquine (1) and quinine (2) cation free radicals [30, 31]. In the compound with the best antioxidant capacity (chloroquine), the SD contributions increase notably in the amine moieties, with values of 0.14 (endo-amine) < 0.15 (exo-amine) < 0.45 (aliphatic amine). The global SD contribution in the quinoline ring is 0.53. Similarly, a comparable pattern of SD contribution is observed for the tertiary amine (0.45) of quinine. However, these values decrease in the following order: 0.01 (endo-amine) < 0.05 (oxygen of methoxy moiety). The global SD contribution in the quinoline ring for quinine is 0.27.

According to the SD contributions, the key differences between chloroquine (1) and quinine (2) are main restrict in the heterocycle rings. The electronic behavior in quinoline rings is closely related to amine, carbinol, chloro or methoxy moieties control. The best SD distributions in chloroquine are observed throughout the entire molecule, but the most significant SD contributions are especially located at the alkylamine. Nonetheless, some properties studied here can be associated with their physical-chemical properties, which, in turn, have implications for their pharmacokinetic and pharmacodynamic effects. In fact, the pKa values of these compounds are 10.18 (1) and 8.50 (2), respectively [38, 39]. Thus, there must be certain structural properties that contribute to the higher pKa value of chloroquine, and its high nucleophilicity and electron donation capacity could be involved in its therapeutic effects.

Impact of nitrogen moieties on electron donation capacity of chloroquine

In the final strategy, all modifications were proposed on the chloroquine structure (Fig. 2). This approach allowed us to observe the individual contributions to the antioxidant capacity of chloroquine by exploring the impact of the chlorine atom and each heteroatom moiety. Two modifications were considered: first, a chloroquine without a chlorine atom (1A); and second, chemical modifications of the amines to hydrocarbons. These molecular modifications were made at the following positions: endo-aromatic (1B), exo-aromatic (1C), trialkyl (1D), and, finally, a molecular modification where only the amino group of the quinoline ring was preserved (1E), with all nitrogen atoms removed (1F). In this way, all possible chemical modifications on the amine moieties of chloroquine to hydrocarbons were evaluated, and the corresponding results can be found in Table 2.

Table 2

Theoretical properties of chloroquine (1) and its related derivatives (1A-1F)
Compound	HOMO (eV)	LUMO (eV)	GAP (eV)	IP (kcal mol^-1)	SET (kcal mol^-1)
1	-5.91	-1.53	4.37	160.48	0
1A	-5.70	-1.28	4.42	157.80	-2.67
1B	-5.37	-1.32	4.04	152.25	-8.23
1C	-5.94	-1.91	4.03	163.36	2.87
1D	-5.90	-1.52	4.38	169.08	8.60
1E	-6.62	-1.90	4.71	185.56	25.08
1F	-6.36	-1.61	4.75	173.85	13.36

From Table 2, the presence of the chlorine atom (1A) and the amine group at the quinoline ring (1B) results in a decrease in the antioxidant capacity of chloroquine. These changes are also associated with an increase in nucleophilicity, as indicated by the HOMO values, and a decrease in ionization potential (IP) for 1A and 1B. Consequently, these compounds exhibit favored single electron transfer (SET) values of -2.67 and − 8.23 kcal mol-1, respectively.

On the contrary, all molecular modifications exclusively on the exo-aromatic (1C) and trialkyl (1D) positions, or a combination of both (1E), lead to a decrease in nucleophilicity according to the HOMO values and an increase in the IP values for 1C, 1D, and 1E. As a result, these compounds demonstrate disfavored SET values of 2.87, 8.60, and 25.08 kcal mol^-1, respectively.

In addition, when all amines are replaced by carbon aromatic or aliphatic groups (1F), the SET value compared to chloroquine is 13.36 kcal mol^-1, attributed to the higher nucleophilicity of the naphthalene ring compared to the quinoline ring. Consequently, the molecule 1B would be an excellent chloroquine derivative, given its superior nucleophilic property (-5.37 eV) and electron donating capacity or ionization potential (152.25 kcal mol^-1). This result aligns with other related derivatives to chloroquine used in antimalarial therapeutic, which lack an aromatic amine, such as halofantrine and lumefantrine [40, 41].

Molecular association between chloroquine and quinine

The molecular association approach was performed by using the most nucleophilic fragments and highest electron donating capacity of both chloroquine (1) and quinine (2), which were highlighted in red. Firstly, two new compounds were proposed as shown in Fig. 5. The results of these molecular associations are described in Table 3.

Our results for design of new derivatives using molecular association between chloroquine (1) and quinine (2) demonstrate that these compounds are more nucleophilic, with higher HOMO values of -5.57 (9) and − 5.42 eV (10), respectively, indicating greater donating electron capacity (Table 3). This is further supported by their lower IP values of 155.42 (9) and 154.51 kcal mol^-1 (10). The SET values were − 5.05 (9) and − 5.98 kcal mol^-1 (10), showing that our strategy was successful.

Table 3

Theoretical properties of chloroquine (1), quinine (2), and associated derivatives (9 and 10).
Compound	HOMO (eV)	LUMO (eV)	GAP (eV)	IP (kcal mol^-1)	SET (kcal mol^-1)
1	-5.91	-1.53	4.37	160.48	0
2	-5.77	-1.73	4.04	162.79	2.30
9	-5.57	-1.23	4.34	155.42	-5.05
10	-5.42	-1.22	4.20	154.51	-5.98

Overall, our theoretical results on quinoline derivatives show that chloroquine has more potent capacity than quinine as electron donating molecule. Quinoline ring is weak when compared to tertiary amine and 4-amine moiety is more important than 6-methoxy group.

A theoretical study on the structure-antioxidant capacity relationship of chloroquine, quinine, and other related derivatives by electron transfer was performed using DFT/B3LYP/6–31 + G(d,p) calculations. Our results revealed a synergistic effect between the amino moieties. Each amine group played a distinct role, with the aliphatic amine demonstrating potent electron donating capacity, the exo-aromatic group showing intermediate antioxidant capacity, and the endo-aromatic group exhibiting the least capacity. The chlorine atom did not significantly contribute to the antioxidant capacity in this study.Chloroquine exhibited a more potent antioxidant capacity than quinine. The p system of the 4-amino-quinoline is more effective than 6-methoxy-quinoline. Additionally, the pKa values were correlated with their high electron donation capacity. The amine moieties had varying impacts on the antioxidant capacity and may also affect other physicochemical properties of quinoline derivatives. Furthermore, we successfully proposed two new strategies for the development of chloroquine derivatives.

Acknowledgments

The authors are grateful to CNPq and CAPES for financial support and fellowship.

Author contribution Conceptualization, Rosivaldo S. Borges; data extraction, Christiane P. O. Aguiar and Igor B. Santos; structure–reactivity, Joyce K. L. Vale; calculations, Vancley S. Borges and Ana C. S. P. S. de Jesus; electronic properties, Christiane P. O. Aguiar and Fernanda P. A. Melo; editing, Daniel S. de Sousa, Alexsandro G. de Sousa and Albérico B. F. da Silva; final version, Rosivaldo S. Borges.

Funding Authors are grateful to CNPq for financial support.

Availability of data and material Not applicable.

Code availability Gaussian 09 software code

G9S016832734579W-5269 N.

Ethics approval Not applicable.

Consent to participate Not applicable.

Consent for publication Yes.

Conflict of interest The authors declare no competing interests.

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Structural requirements for nucleophilicity and antioxidant capacity on quinoline derivatives: a theoretical study

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Version 1

Abstract

Context

Methods

Figures

Introduction

Methodology

Molecular calculations

Structural approaches

Results and Discussion

Electron donation capacity of chloroquine related to quinine

Impact of nitrogen moieties on electron donation capacity of chloroquine

Molecular association between chloroquine and quinine

Conclusions

Declarations

References

Additional Declarations

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