New Halogen-Containing Drugs Approved by FDA in 2021: An Overview on Their Syntheses and Pharmaceutical Use

Introduction

In the last years, new halogen-containing drugs have emerged. In 2021, 14 new chemical entities (Table S1) were approved by the FDA for clinical use [1]. In the previous year, the very same number of halogenated molecules reached the market [2]. These data highlight two aspects: from one side, a big effort in searching for new therapies has been done despite the COVID-19 pandemic, and from the other, the use of halogens is becoming regular in medicinal chemistry.

Not only synthetic compounds but also halogenated natural products are worth mentioning, since they display a broad range of biological activities (e.g., antibacterial, antifungal and anticancer) [3]. As an example, vancomycin (Figure 1) is a clinical, chlorine-containing antibiotic obtained from the bacterium Streptomyces orientalis, which is mainly used to treat methicillin-resistant Staphylococcus aureus (MRSA) infections [4].

Another very important class is marine algae that have been largely investigated in the last few decades given their ability to produce halogenated metabolites with potential use, among the others, in the pharmaceutical industry [5]. In this particular case, chlorine and bromine appear often in biologically active metabolites, whereas iodine and fluorine remain quite unusual within the chemical structures [6]. It is interesting to note that bromine is more frequently present as a substituent in algae organohalogenated compounds in spite of chlorine being more concentrated than bromine in sea water [5].

Opposite to this trend, fluorine is prevalently employed in modern medicinal chemistry [7]: eight approved drugs out of 14 in 2021 were fluorine-containing drugs, four contained chlorine and two contained a combination of the two halogens. Thirteen new fluorinated drugs were approved by the FDA in 2020 for commercial use [8]. None possessed bromine or iodine. For this reason, we will confine our topic to fluorine and chlorine only. Only a few examples in the literature have reported fluorine in natural organisms. Fluoroacetate and some fluorinated fatty acids have been reported, for instance, in actinomycetes species [9].

In this review, we will briefly describe the chemical properties of halogen atoms in order to justify the predominance of -F and -Cl in drugs. Moreover, we will provide the chemical synthesis of the 14 approved halogenated drugs in 2021.

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Benedetto Tiz, D.; Bagnoli, L.; Rosati, O.; Marini, F.; Sancineto, L.; Santi, C. New Halogen-Containing Drugs Approved by FDA in 2021: An Overview on Their Syntheses and Pharmaceutical Use. Molecules 2022, 27, 1643. https://doi.org/10.3390/molecules27051643

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