Halogen-Containing Drugs in 2025: A Record Year for the Therapeutic Use and Synthesis of FDA-Approved Small Molecules

Abstract

Halogens, particularly fluorine, chlorine, and bromine, play a pivotal role in modern drug discovery and development. Their incorporation into drug molecules significantly influences physicochemical properties, including lipophilicity, metabolic stability, and target binding affinity. Fluorine, the most commonly used halogen, enhances bioavailability and receptor interactions, as seen in several blockbuster drugs. Chlorine and bromine contribute to hydrophobic interactions and modulate pharmacokinetics, while iodine is less frequently utilized due to its larger atomic size and reactivity. The strategic placement of halogens in drug scaffolds has led to the success of numerous FDA-approved pharmaceuticals across therapeutic areas, including oncology, infectious diseases, and central nervous system disorders. This review explores the structure–activity relationships (SAR) of halogen-containing drugs, highlighting recent approvals (2025), their synthesis (with yields, when available), therapeutic use, and, when experimentally available, the interaction with their biological target macromolecules.

Introduction

In our previous works [1,2,3,4] and especially in [1], we have highlighted the emergent role of halogens and, in particular, of fluorine and chlorine in the preparation of drugs for the treatment of several diseases, such as viral infections, several types of cancer, cardiovascular disease, multiple sclerosis, migraine, and inflammatory diseases such as vasculitis. Talking about numbers, we showed that 14 of the 50 molecules approved by the FDA in 2021 contained halogens. In 2022, only six drugs approved contained halogens [5]. In 2023, the number rose to 14 [5]. More recently, namely in 2024, the U.S. Food and Drug Administration (FDA) approved 50 new drugs, of which 16 contain halogen atoms such as fluorine and chlorine. Therefore, it is evident that halogens play a significant role in drug discovery and development due to their impact on the pharmacological properties of compounds [5].

The review by Ali et al. [5] highlights the importance of fluorine and chlorine in medicinal chemistry, discussing their properties and how they influence drug profiles. The authors provided detailed information on each halogen-containing drug approved in 2024, including: trade name, active ingredients, route of administration, approval date, indication, and mode of action. The 16 halogen-containing approved drugs in 2024 are shown in Figure 1: tovorafenib 1 (fluorine-based), vorasidenib 2 (fluorine- and chlorine-based), inavolisib 3 (fluorine-based), revumenib 4 (fluorine-based), ensartinib 5 (fluorine and chlorine-based), arimoclomol 6 (chlorine-based), crinecerfont 7 (fluorine and chlorine-based), tezacaftor 8 (fluorine-based), flurpiridaz F18 9 (fluorine- and chlorine-based), iomeprol 10 (iodine-based), resmetirom 11 (chlorine-based), seladelpar 12 (fluorine-based), vadadustat 13 (chlorine-based), danicopan 14 (fluorine- and bromine-based), aprocitentan 15 (bromine-based), acoramidis 16 (fluorine-based) [6]. Importantly, the majority of approved drugs contain at least covalently bound fluorine, which is often combined with another halogen (most often chlorine or bromine). Only one drug, iomeprol, contains iodine. Among fluorine-containing drugs, trifluoromethyl groups are encountered in three drugs (1, 2, and 12). Aromatic single-atom fluorine is present in five drugs (4, 5, 7, 8, and 16). Aliphatic-type fluorine is contained in 3, 8, 9, and 14. Moreover, 9 is a novel positron emission tomography (PET) myocardial perfusion imaging tracer [7].

This trend, that is, the majority of approved drugs contain fluorine or chlorine, is confirmed by our analysis presented in Figure 2. The bar charts were created using data retrieved from PubMed using the general terms “fluorine approved drugs” [8], “bromine approved drugs” [9], “chlorine approved drugs” [10], and “iodine approved drugs” [11] in the period of 2000–2025. The arithmetic sum of each halogen contribution is reported. It appears that fluorine and chlorine are dominating in terms of number. Iodine also yielded a high number of hits. This could be explained by the fact that many advanced radioactive iodine therapeutics are in the pipeline.

Ali’s [5], our [1] work, and many other comprehensive reviews [12,13] have previously shown that the careful addition of fluorine or fluorine-containing groups (e.g., CHF2, CF3, OCF3) to electron-rich heteroaromatic and aromatic rings or olefins that are vulnerable to oxidation may result in greater metabolic stability. Fluorine can increase metabolic stability by acting as an isostere of carbonyl groups, eliminating reductive reactions [14]. Moving to physicochemical parameters, adding fluorine to aryl or vinyl moieties increases their lipophilicity. In contrast, adding fluorine to an aliphatic system diminishes lipophilicity [15].

Chlorine can serve as a bioisostere for several functions, including halides (F, Br, I), monovalent substituents (OH, SH), and pseudohalides (CF3 and CN) [16]. Chlorine’s similar physicochemical qualities allow it to operate as a bioisostere of methyl groups, improving metabolic stability in vivo [5]. Chlorine is a more effective halogen bond donor than fluorine due to its bigger size [17]. According to certain literature, the addition of bromine can increase the affinity and binding strength to its target via halogen bonds [18]. While bromine has potential properties, other studies suggest it can have negative consequences on the human body [19].

Iodine isotopes have potential for drug discovery and development, but their instability in the body due to weak bonds with organic molecules limits their usage [5]. Interestingly, one iodine-containing drug (iomeprol 10) was approved in 2024 as a contrast agent.

In the last year (2025), several halogen-containing small molecules (MW < 600 Da) were approved by the FDA. In the next sections, the novel drugs (“novel” drugs are new drugs never before approved or marketed in the U.S. [20]) will be presented according to their date of approval. For each molecule, a notable synthetic pathway (those from the inventors will be privileged) will be given together with the therapeutic indication.

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Benedetto Tiz, D.; D’Alì, M.; Iraci, N.; Santi, C.; Sancineto, L. Halogen-Containing Drugs in 2025: A Record Year for the Therapeutic Use and Synthesis of FDA-Approved Small Molecules. Biomolecules 2026, 16, 381. https://doi.org/10.3390/biom16030381

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