1. Introduction

Medicine is the frontline in humanity’s ongoing battle against disease. Over the years, advancements in drug discovery have vastly improved the quality of life for countless patients worldwide. New discoveries in this region often bring hope, helping individuals step out from conditions that were once deemed untreatable, and the key to these successes relies on organic chemistry subject's development. In numerous experiments in organic chemistry labs, researchers have found something impressive: the 'magic' modifications, such as replacing a hydrogen atom in an aromatic ring with chlorine [1,2]. It has attracted the attention of researchers and medical researchers due to its unique properties, this small structural change has been found able to make great change, it enhances a drug’s effectiveness.

The magic property of adding chlorine to aromatic rings in drugs has opened new doors in medicinal chemistry. Halogen group elements have unique properties that can influence how a drug molecule interacts with its target [3]. Chlorine is one of the halogen families. Cell membranes are typically considered a major barrier for molecules. They are made up of hydrophobic tails and hydrophilic heads, which align to prevent hydrophilic molecules from passing through. By replacing a hydrogen atom with a halogen, the highly electronegative halogen pulls electrons toward itself, decreasing the charge on the aromatic structure. This shift in charge lowers the molecule's reactivity with hydrogen bonds in water, resulting in a more hydrophobic molecule.

Once the drug molecule becomes more hydrophobic, it can more easily cross cell membranes [4]. This charge shift also helps the molecule bind more effectively to its target proteins. Many proteins have hydrophobic binding pockets. For this reason increasing the hydrophobicity of the drug molecule could increase affinity. This ensures that enough drug molecules attach to the correct target. This process ensures drug compounds in the patient body maintain high efficiency even at lower concentrations. Halogen's influence also includes improving a drug's metabolic stability. Metabolic stability is the susceptibility of compounds to biotransformation. Metabolism refers to all the biochemical processes that occur in the body to maintain life, including breaking down nutrients for energy, synthesizing necessary compounds, as well as processing and eliminating chemicals, including drugs and toxins. Metabolic stability is the ability to resist a drug or other chemical compound by being broken down or metabolized in the body. Halogen elements usually give drugs a higher metabolic stability that helps the drug remain active in the body for longer periods. The constant residency allows the drug molecules to constantly influence the patient. All these properties have the potential to make a drug more powerful.

While metabolic stability is a double-edged sword, it helps drugs remain active longer in the body and this also means that the drug can be harder to clean from the system when it’s no longer needed. Chlorine’s increased hydrophobicity can sometimes lead to unexpected accumulation in fatty tissues, which may affect the drug’s distribution and clearance. In other words, chlorine-containing drugs have the potential to increase toxicity and lead to harmful byproducts during metabolism. In summary, while chlorine may enhance a drug's performance, it requires careful balancing to avoid potential side effect.

2. Mechanism of action of chlorine substitution

Chlorine is located on the right side of the Periodic Table. It is under fluorine which indicates a more moderate compared to fluorine but still strong electronegative atom with a relatively small electron cloud.

In π-conjugated systemsπ-electrons are delocalized across the aromatic ring. This means the electrons do not belong to a single bond. They are shared across multiple adjacent p-orbitals. The electron density in these systems is distributed over the entire conjugated network, making it sensitive to any substituents attached to the ring. When chloride is introduced into an aromatic ring, chlorine's electron-withdrawing nature affects not only the carbon it is attached to, but the electron density distribution across the whole molecule. Nucleophiles are species that donate an electron pair to form a new chemical bond and Electrophiles are species that accept an electron pair to create a new bond, both of them tend to react with electron-rich areas in molecules. The chlorine withdrawal of electron density from the aromatic ring that the drug molecule reduces reactions with nucleophiles or electrophiles in biological environments, thus enhancing the drug's chemical stability.

The presence of a chlorine atom increases the overall hydrophobic character of the molecule. Research has indicated that many key protein targets, including enzymes and receptors, possess hydrophobic regions that are optimized for interactions with non-polar ligands. Chlorine increases its binding affinity to these hydrophobic pockets, which can lead to more effective inhibition or activation of the target protein. For instance, studies have demonstrated that the binding affinity of kinase inhibitors improves significantly with the addition of halogen substituents, usually chlorine, due to these non-covalent hydrophobic interactions.

3. Impact of chlorine substitution on drug molecules

Neurological drugs often target nonpolar or hydrophobic binding sites [5,6]. For example, many neuroreceptors and ion channels are located in the lipid-rich environment of cell membranes, chlorine atom increases the overall hydrophobic character of the molecule therefore its binding affinity increase to these hydrophobic pockets, which can lead to more effective inhibition or activation of the target protein.

Some other drugs targeting the cardiovascular system often interact with more polar or charged receptors, such as those involved in ion transport or enzyme regulation. These interactions may rely more on polar or ionic interactions than purely hydrophobic contacts. Chlorine modifications can still be beneficial due to the metabolic resistance, their effectiveness may vary depending on the target's specific characteristics. A paper proved this claim. In the kidney, the macula densa is a structure that senses salt levels, uses chloride to help regulate fluid and salt levels in the body. A protein called WNK acts as a chloride sensor in the body, and when chloride levels are low, it leads to increased activity transporters NKCC and NCC that help reabsorb sodium, potassium, and chloride [7]. This may cause more fluid to be retained, which worsens HF and reduces the effectiveness of diuretics. The research demonstrates, chloride's influence on key electrolyte transporters sodium-potassium-chloride cotransporters (NKCC) and sodium-chloride cotransporters (NCC) explain how Chlorine-containing drugs important in the cardiovascular system's fluid regulation and ion homeostasis.

Researchers have already conducted many studies into chlorine’s magic effect. In a paper that introduces the effect of “magic chlorine”, the researchers chose to target various FDA-approved drugs, such as diazepam, chloroquine, chloramphenicol, and bendamustine, use computational techniques, density functional theory (DFT), to model the inhibitors with and without chlorine substitutions and evaluated their physicochemical properties, pharmacokinetics, and toxicity. The evaluation suggests a clear idea that one or two chloride substitutions could increase most inhibitors' molecular physicochemical properties and improve their stability. In addition, the toxicity effect should be considered, researchers give the clear conclusion that most of the molecules in this research are confirmed by the FDA and do not show any toxicity in four degrees, the mutagenicity, tumorigenic, irritant, and reproductive. The conclusion may not be enough to apply to all new chlorine substitution molecules. But the current medical chloride substitution drug is safe. Follow by professional guidance, patients do not have to worry about toxicity in chloride.

4. Chlorine’s role in drug stability and biotransformation

A study about cytochrome P450-mediated and aromatic hydroxylation interaction from Zhao et al. explains this [8]. Cytochrome P450-is a family of enzymes responsible for the Phase I metabolism of many drugs, primarily through oxidation reactions. Researchers found that chlorinated aromatic compounds can form activation barriers. The investigation reveals it is caused by the electron-withdrawing ability of chlorine, which stabilizes the transition state and reduces reactivity, thereby supporting the strategy of using halogens like chlorine to enhance drug stability. In simple terms, Chlorination of the aromatic ring decreases the electron density available for oxidation reaction, reducing the site accessible to enzymatic attack. This protective effect increases the metabolic stability of the drug, allowing it to maintain therapeutic concentrations in the body for longer durations.

The effect of chlorination on metabolic stability is well-documented in drugs like chlorpromazine, a typical antipsychotic. This drug contains multiple chlorine atoms that decrease the likelihood of aromatic hydroxylation. As a result, the drug persists longer in the body, allowing for a sustained therapeutic effect.

The metabolic travel of drugs is not only one phase. Once a drug or its metabolites undergo Phase I metabolism, they typically proceed to Phase II metabolism. Here, drug conjugation reactions occur to further increase solubility and facilitate excretion. After their metabolism process would be able to combine the waste compound together and throw it out with excretion.

In the context of chlorinated drugs, Phase I metabolism delay will impact phase II. In phase I, metabolic enzymes may not introduce hydroxyl groups as readily due to the chlorination decreasing the reactivity of the molecule. Since Chlorinated molecules are less reactive, metabolic enzymes may not introduce hydroxyl groups as readily during Phase I metabolism, resulting in fewer polar metabolites. These metabolites are the target of phase II metabolism. If Phase I metabolism is slowed, fewer metabolites are available for Phase II processing. This limited transformation in Phase I makes the drug persist in its original form for longer periods. Drugs may become more active, less active, or toxic after Phase I metabolism. New compounds formed during metabolism are mostly excreted after Phase II metabolism. In Phase II metabolism involves conjugation reactions such as glucuronidation-attaches glucuronic acid to the drug molecule, sulfation-transfers a sulfate group to the drug, and acetylation-adds an acetyl group on the drug. Conjugation reactions introduce hydrophilic structure to the drug molecule. These groups increase the molecule's ability to interact with water molecules through hydrogen bonding. After phase II, drug molecules decrease the lipid solubility, reducing its reabsorption in the renal tubules, increasing their water solubility to facilitate excretion via urine or bile.

However, this is only one situation after injecting chlorine into a drug molecule. By incorporating a chlorine atom, the drug’s stability can sometimes be improved by decreasing the oxidation reactions. Chlorination can decrease the reactivity of the molecule toward metabolic enzymes, thus prolonging its active form in the body. The effect of chlorination on drug metabolism is complex and can vary depending on the specific drug and the enzymes involved. Wang et al. (2019) Conducted a specific experimental and computational study on how halogen substitution effects ketamine metabolism by CYP2B6. The results indicate that chlorination of ketamine increased its binding affinity to CYP2B6, enhancing Phase I metabolism rather than decreasing it. Based on the conclusion of this experiment, researchers proved Chlorination does not always reduce Phase I metabolism, instead. In some conditions its impact depends on the molecular structure and the metabolic pathways of the specific drug.

Two papers show that different enzymes and compound structures lead to different results. Chlorination Ketamine forms a suitable Hydrophobicity, therefore it could combine CYP2B6 enzymes faster, resulting in a faster metabolism. In Zhao’s paper [9], chlorination reduces the electron density of drug molecules, decreasing their reactivity toward cytochrome P450 enzymes and leading to reduced oxidation reactions. Those two papers show different results, they both confirm that chlorine and other halogen elements are useful in adjusting the electronic and hydrophobic properties of drug compounds, further influencing their metabolism.

5. Chlorine’s potential risk

Metabolic resistance doesn't always bring good results. Recent research sheds light on the effects of chlorinated drug compounds on metabolism, specifically showing how these compounds can delay or interfere with Phase II metabolism, raising risks related to drug accumulation and toxicity. Chlorine substitution in drug molecules creates resistance to oxidation reactions to enhance metabolic stability. Therefore it can impact the progression through metabolic phases.

Such effects need to be concerned for drugs with chronic use profiles or those taken at high doses. The accumulation of chlorinated drugs has potentially caused unexpected danger. They increase the body's metabolic load to clear the compound effectively. Over abuse chronic could pollute the water environment.

This is not groundless speculation. A well-known example is chlorinated paraffins. It is an organic compound used in many factory applications. In biological processes, it exhibits reduced rates of enzymatic breakdown allowing them to persist longer within biological tissues that lead to bioaccumulation in organs which handle most drug clearance like the liver and kidneys potentially causing tissue stress and toxic effects over time [10]. Research on chlorinated paraffins is limited because they usually occur as complex isomers, and researchers lack an agreed-upon reference method. If this example alone does not fully demonstrate the risks following with chlorinated molecules, a paper discussing the bioaccumulation, metabolism, and toxicity of fluoroquinolones in aquatic environments specifically highlights how these antibiotics persist and accumulate in organisms and their tissues.

Fluorance is also a halogen element with close chemistry priority with chloride. Fluoroquinolones also have a classical structure as chlorinated drug, a fluorance attached at the aromatic ring, which indicates they share the same mechanism of chlorinated drug.

Due to the same reason, Flounce is comparable to chlorinated drugs that resist metabolic breakdown, leading to prolonged retention in the body and potential accumulation in tissues.

The study mentions that Fluoroquinolone's structure is the main reason for toxicity. The fluorine substituent affects their bioaccumulation and metabolic pathways in aquatic organisms. To make comparison, Chlorine substitutions in drugs can also enhance metabolic stability and decrease reactivity toward enzymes. The paper also focuses on the toxicity of Fluoroquinolones and their metabolites in organisms. Some metabolites are toxic and may even more harmful than the parent compounds, especially when they accumulate in high concentrations. In the context of chlorinated drugs, delayed Phase II metabolism can also leave metabolized compounds stacked in the body, the phase I and phase II metabolic processes are delayed by resistance leading to similar toxic risks when these compounds accumulate in tissues.

Given these similarities, it is reasonable to conclude that chlorinated drugs could lead to environmental and biological harm similar to that caused by fluoroquinolones. This conclusion makes researchers aware that chloride is not the docile and priceless universal enhancement in biochemistry and drug design.

6. Conclusion

This article introduces chlorine substitution in drugs. Through addition of chlorine atoms into aromatic rings, the hydrophobicity of the drug is enhanced, allowing it to more effectively cross cell membranes and bind to hydrophobic targets within proteins. This modification also improves drug molecular metabolic stability, making it more resistant to enzymatic degradation, thereby boosting the long-term therapeutic effects. The results of this study have implications for medicinal chemistry because it brings attention to both advantages and disadvantages in chloride substitution which help improve drug design strategies to maximize efficacy while minimizing adverse effects.

This study has its limitations. It does not discuss the differences in enzyme interactions between different drug types, nor does it deeply explore the long-term effects of chlorine accumulation in the body. The effects of other halogens and their comparative impact on drug properties also require further investigation to draw broader conclusions.

Future study will focus on exploring the metabolic pathways affected by chlorine substitution in more detail, the interactions between different enzymes and halogen-modified drugs. Comparative studies of other halogens can provide more insight into the specific advantages and disadvantages of chlorine and other halogens modifications.