Key contemporary considerations for halogens in drug discovery

Halogens (F, Cl, Br, I), especially F and Cl play a vital role in contemporary drug discovery. For instance, around 25% of approved drugs and 40% of lead molecules possess halogens [1]. Moreover, most blockbuster drugs are also small molecules featuring halogen atoms. Our analysis of the FDA-approved drugs from 2018 to 2024 shows that 108 out of 352 approved drugs are halogen-containing small molecules [1]. In 2025, the FDA has already approved a total of 46 drugs, including 30 small molecules and 16 macromolecules [2]. Intriguingly, 16 out of the 30 small molecules contain halogen atoms, primarily F, Cl and I, highlighting their continued importance in drug discovery and development.

Halogens, particularly F and Cl have a remarkable ability to alter the properties of drug molecules. Therefore, F and Cl both can be effectively exploited in contemporary drug discovery to identify novel drugs. For example, prudent positioning of a F atom or its substituents such as CF₃, OCF₃ and CHF₂ in a drug molecule can result in enhanced potency and permeability, diminished clearance, reduction in the pKa of neighboring functional groups and conformational locking with improved pharmacokinetic (PK) and pharmacodynamic (PD) properties [3]. The potency and target selectivity can also be significantly improved through meticulous incorporation of a F atom in a drug molecule by modulating hydrophobic interactions, lipophilicity, conformation, and pKa [4]. Additionally, introduction of a F atom can improve drug permeability by enhancing lipophilicity, attenuating the basicity of neighboring functionalities, and installing a F atom at the ortho position to an NH group on aromatic systems [5–7]. One of the interesting properties of F is its ability to modulate the lipophilicity of a molecule. The C–F bond is highly polar due to the strong electronegativity of fluorine, but its impact on lipophilicity is context-dependent. In aliphatic systems, fluorine often increases polarity, which can reduce lipophilicity by enhancing dipole–dipole interactions and hydrogen bonding with the solvent [8,9]. In contrast, in aromatic systems, fluorine is less polarizable and contributes less to overall molecular polarity; instead, it can increase lipophilicity through favorable hydrophobic interactions and π–π stacking with the aromatic system [8,9]. Further, F holds great potential to modulate the pKa of neighboring functional groups and the electron density of aromatic and heteroaromatic frameworks due to its robust electronegativity. Modifying the pKa of a molecule may alter its potency, selectivity, toxicity, lipophilicity, as well as its PK properties such as absorption, distribution, metabolism, and excretion (ADME) [4]. Because of the robustness of the C-F bond, F is routinely utilized to enhance the metabolic stability of drug molecules. To address poor metabolic stability, metabolically labile hydrogen atoms can be replaced with F on aromatic as well as aliphatic moieties. Since the size of fluorine (van der Waals radius = 1.47 Å) to hydrogen (van der Waals radius = 1.20 Å) is relatively similar, replacing a F atom with hydrogen in a molecule generally does not induce substantial conformational changes, thereby maintaining the critical interactions with drug targets necessary for biochemical activity. The metabolic stability of electron-rich aryl and heteroaryl frameworks, as well as olefins, can be significantly increased by strategically incorporating a F atom or its substituents at positions susceptible to oxidation. F can be used as an isostere of carbonyl functionality, thereby increasing the metabolic stability of a drug. Trifluoromethyl (CF₃) and difluoromethyl (CHF₂) groups are highly prevalent in the FDA-approved drugs. Swapping CH₃ with CF₃ in a drug molecule may result in increased potency by enhancing interactions with carbonyl, carboxylic acid, and hydroxyl residues within the target proteins. In addition, CF₃ group is capable of increasing permeability and metabolic stability, reducing pKa of neighboring groups, and locking the conformations of drug molecules [10]. Recently, CHF₂ group has shown great potential to operate as a bioisostere of CH₃, hydroxy, and thiol groups. One of the powerful applications of fluorine is the use of its isotope fluorine-18 in drug discovery and development. For example, fluorine-18 (¹⁸F)-containing molecules have been extensively used as diagnostic agents in positron emission tomography (PET) to detect and validate various human diseases. Recent reports revealed that the FDA approved five ¹⁸F-containing radioligands as diagnostic agents, including Flotufolastat F-18 gallium, Fluoroestrdiol F-18, Fluorodopa F-18, Flortaucipir F-18, and Piflufolastat F-18 between 2019 and 2023. Furthermore, Flurpiridaz F-18 was approved by the FDA as a diagnostic agent for PET imaging in 2024 [11].

By 2019, more than 250 FDA-approved chlorine-containing molecules were available on the market for clinical use, underscoring its significance in pharmaceutical research. Judicious substitution of a single hydrogen atom with a Cl atom in drug molecules may significantly improve potency, binding affinity, selectivity, cell permeability, as well as PK properties. Literature survey reveals that replacing a hydrogen atom with a Cl atom can improve the potency of drug molecules by up to more than 1000-fold and, in some cases, even up to 100,000-fold [12]. Chlorine can serve as a bioisostere for a variety of functionalities, including OH, SH, F, Br, I, CF₃ and CN [13]. Additionally, it can act as a bioisostere for the CH₃ group, enhancing the in vivo metabolic stability of drug molecules. The size of a chlorine atom and a CH₃ group is comparable when considering refractivity (polarizability) values of 6.03 and 5.65, respectively [14,15]. Additionally, chlorine and CH₃ can be considered isolipophilic based on their π coefficients of 0.71 and 0.56, respectively [14,15]. However, their steric A-values differ significantly, 0.43 for chlorine and 1.70 for CH₃, indicating that chlorine is considerably smaller than a methyl group [16]. Another notable feature of chlorine is its ability to form halogen bonds, which can strengthen ligand-protein interactions and thereby improve drug efficacy [17]. Cl is widely used in drugs, which contain olefins and aromatic or heteroaromatic moieties; however, it is not typically advisable to install Cl into the aliphatic portion of a drug, as it may react with nucleophilic groups of proteins via nucleophilic substitution, potentially leading to off-target toxicity. Nevertheless, there are many aliphatic chlorides with remarkable stability. For instance, sucralose (Splenda) is a densely chlorinated compound that is excreted from the body largely unchanged, with about 11–27% recovered in its original form [18]. This suggests that both primary and secondary chlorides in sucralose are stable in vivo. Additionally, drugs such as alclometasone, clindamycin, and beclomethasone have secondary or tertiary alkyl chlorides that do not display covalent reactivity.

Bromine and iodine have historically seen limited use in drug discovery and development. Nevertheless, the FDA approved four bromine-containing drugs in 2020 and two more in 2024 [1]. For iodine-containing drugs, the FDA approved Iomeprol in 2024 and Mirdametinib in 2025. Like Cl and I, Br can also form halogen bonds with proteins, thereby enhancing the binding strength and affinity of drug molecules [19]. Consequently, it may elevate the duration of action of a drug, which in turn can improve its efficacy. The van der Waals radius of Br (~1.85 Å) lies between that of I (~1.98 Å) and Cl (~1.75 Å). Within a specific binding pocket, I may be sterically incompatible, leading to unfavorable clashes, whereas Cl may be insufficiently large to fully occupy the available volume, resulting in suboptimal van der Waals interactions. Br therefore provides an optimal balance, enabling efficient space filling while avoiding steric strain. One of the notable applications of Br is the use of its isotopes in radiotherapy as well as in diagnostic imaging. Due to the long half-life of ⁷⁶Br (t_1/2 = 16.2 h), it can be effectively used to assess metabolic pathways at later time points. Iodine isotope-containing molecules often demonstrate limited stability in the body due to the relatively weak C-I bond, which impedes their utility in drug discovery and development. In contrast, because the C-Br bond shows greater strength than the C-I bond, ⁷⁶Br-labeled molecules display improved in vivo stability and are suitable for PET imaging applications. Iodine isotopes (e.g., ¹²³I, ¹²⁴I, ¹²⁵I and ¹³¹I)-labeled molecules have been used in PET imaging as well as in single-photon emission computed tomography (SPECT). For instance, the ¹²³I-labeled ligand (¹²³I-2β-carboxymethoxy-3β-[4-iodophenyl] tropane measures dopamine transporter availability, thereby assisting in the diagnosis of Alzheimer’s disease [20]. ¹²⁴I-labeled ligands, including 1-(4-iodophenyl)-3-(2-adamantyl)guanidine (¹²⁴I-IPAG) and 5-[¹²⁴I] iodo-2-deoxyuridine (¹²⁴I-IUdR) have been exploited in PET imaging [21,22]. ¹²⁵I possesses relatively low energy, which restricts its use in imaging applications. Nevertheless, it has been utilized for developing novel nuclear medications [23]. Overall, iodine isotopes have demonstrated significant potential for both the treatment and diagnosis of diverse human diseases. Hypervalent iodine reagents also hold great potential for the selective functionalization of proteins. For example, they are leveraged in executing the late-stage functionalization of peptides and proteins owing to their high stability and tolerance in bio-compatible environment. In addition, hypervalent iodine reagents have shown potential to act as a “group transfer” reagent, transferring a covalent warhead to the specific residue within the degraders (e.g., PROTACs), thereby transforming them from undruggable to druggable [24].

A large number of halogen-containing investigational new drugs (INDs), especially those incorporating F and Cl are currently being evaluated in distinct phases of clinical trials [25]. Some representative F and Cl containing INDs are briefly discussed here. Seltorexant, a small molecule containing a F atom is a selective orexin-2 receptor antagonist. It is being investigated in phase III to assess its safety and efficacy as an adjunctive therapy, compared with placebo, for patients with major depressive disorder and insomnia symptoms (NCT06559306). Bitopertin, which contains a F atom and two CF₃ groups, is a glycine transporter 1 (GlyT1) inhibitor. It is in phase III to examine its safety, tolerability and efficacy in patients suffering from erythropoietic protoporphyria (EPP) or X-linked protoporphyria (XLP) (NCT06910358). AZD0022 is a reversible KRAS(G12D) on/off inhibitor that contains four F atoms positioned at different sites within the molecule. Phase I/II studies of AZD0022 are underway to investigate its safety, efficacy, tolerability and PK as a monotherapy or in combination with anticancer drugs in patients with tumors harboring a KRASG12D mutation (NCT06599502). VVD-130037 containing a Cl atom is an active covalent activator of Kelch-like ECH-associated protein 1 (KEAP 1). It is under study in phase I to test its safety, efficacy and tolerability in patients with advanced solid tumors (NCT05954312). BAY 3389934 is a selective dual factor IIa/Xa inhibitor that has a Cl atom. Phase I study of BAY 3389934 is being conducted to examine its safety and efficacy at elevated doses in healthy volunteers in Japan (NCT07176728). Dabogratinib (TYRA-300) that contains two Cl atoms is a selective inhibitor of fibroblast growth factor receptor 3 (FGFR3). It is in phase IIa/b to assess its safety and efficacy in subject with low grade upper tract urothelial carcinoma (NCT07265947). GB1211, small molecule having three F atoms and a Br atom is a galectin-3 inhibitor. Phase II study of GB1211 is underway to evaluate its objective response with pembrolizumab against pembrolizumab and placebo in people suffering with advance metastatic melanoma or head and neck squamous cell carcinoma (NCT05913388).

Several key aspects should be considered during contemporary rational drug design when incorporating halogen atoms into the molecules: (1) Halogens, particularly Cl, Br, and I, can participate in halogen bonding, a non-covalent interaction of the kind A–X···B–A′, where X is a halogen atom and B is an electron-donating atom or group. This interaction arises from the presence of a σ-hole on the halogen atom X, which is generated by an anisotropic distribution of electron density along the A–X bond. The positively polarized σ-hole located on halogen interacts attractively with the electron-donating moiety B. In the context of drug-target interaction, a halogen present on a drug molecule can interact with nitrogen, sulfur, oxygen atoms of carbonyl or hydroxy groups within the target, thereby enhancing potency, selectivity, and binding affinity. (2) Halogens can modulate the physicochemical properties of drug molecules. For instance, incorporating halogens into a molecule, especially F and Cl, typically enhances lipophilicity, thereby increasing permeability and oral absorption. The electron density of aromatic or heteroaromatic systems, as well as pKa of proximal functional groups, generally decrease upon addition of halogens, particularly F due to their high electronegativity. These electronic changes can improve membrane permeability and target affinity. Amine basicity increases with carbon homologation as the distance between the amine nitrogen and the fluorine atom increases [26]. Installation of a fluorine atom to the β-carbon results in a −1.7 pKa unit shift, whereas substitution at the γ-, δ-, and ε-carbon positions lead to progressively smaller decreases of −0.7, −0.3, and −0.1 pKa units, respectively. This relationship can be exploited to precisely modulate the basicity of alkylamines. Because halogens are relatively large, adding a halogen atom may change the shape of a molecule or make it bulkier, enabling it to better occupy a specific region of the binding pocket and protect a metabolic soft spot. (3) Halogens, particularly F and Cl, play a pivotal role in modulating PK and PD properties of drug molecules. Appending F or Cl atoms into a drug molecule may increase its metabolic stability, thereby enhancing its half-life in the body. Halogen may alter a drug’s distribution and half-life in the bloodstream, partly due to halogen bonding between halogens and plasma transport proteins. (4) Artificial intelligence (AI)-powered platforms, particularly machine learning and deep learning, can help identify optimal sites withing drug molecules for halogen incorporation, thereby accelerating the discovery of novel halogen containing therapeutics [27]. For example, Neural network models are trained on large datasets of high-level quantum mechanical calculations (e.g., MP2/TZVPP) to identify the σ-hole driven interaction under specific geometric limitations. These models enable the detection of the σ-hole and the surrounding belt of high lateral electron density perpendicular to R-X bond axis wit high accuracy [28].

Densely halogenated substances are typically not biodegradable and are therefore classified as persistent organic pollutants. Owing to their high lipophilicity, they readily accumulate in fatty tissues, thereby causing bioaccumulation throughout the food chain and long-term environmental contamination [29]. The synthesis of halogenated aliphatic compounds requires the use of highly toxic, corrosive, and reactive species, involving elemental chlorine, fluorine or hydrogen fluoride. These synthetic processes often demand highly specialized equipment with strict temperature and pressure control, as well as corrosion-resistant materials, to safely handle extremely exothermic reactions [30]. If not properly managed or disposed of, these substances can be released into water, air and soil. In industrial settings, their degradation is often achieved through incineration or high-temperature treatment, which can result in the release of toxic gases, including hydrogen fluoride, hydrogen chloride and hydrogen iodide.

In conclusion, the high prevalence of halogens in the FDA-approved drugs and in the many INDs currently being evaluated across various phases of clinical trials underscores their importance in drug discovery and development. Halogens, particularly the heavier halogens (Br and I), can be leveraged in contemporary drug discovery beyond the constraints of Lipinski’s rule of 5 (Ro5). In these contexts, halogens act as precise, directional interaction element within complex chemical spaces, including PROTAC degraders and macrocyclic scaffolds. Traditionally, both F and Cl have been incorporated primarily to improve metabolic stability and modulate lipophilicity. In contrast, emerging tactics increasingly exploit heavier halogens, especially Br and I, to engage in halogen-bonding, thereby enabling confirmational control and improved target selectivity, including for targets previously considered undruggable. Given their great potential and unique features associated with druglike molecules, halogens are expected to continue playing a key role in contemporary drug discovery and development, contributing to the creation of novel, life-changing medicines for the treatment of numerous human diseases in the near future.