All4Nutra
Abstract
Sulfur and phosphorus are elements that can be found in various FDA-approved drugs, either as part of the active pharmaceutical ingredients (APIs) or as components of excipients (inactive ingredients). In this review we will explore the therapeutical use and the synthesis of the approved small molecules (<1000 Da) in the last five years. Sulfur contributes to the redox properties of drugs, the ability to form disulfide bonds, and hydrophobicity, influencing drug interactions and efficacy. Phosphorus contributes to the charge, polarity, and binding affinity of drugs, enhancing their activity in biological systems. These two elements have been increasingly incorporated into therapeutic agents, enhancing drug efficacy, selectivity, and pharmacokinetic profiles. 33 sulfur-based and 3 phosphorus-based drugs are described in this paper. The therapeutic uses and the synthesis of the S- and P- containing approved drugs will be given.
Introduction
Over the last several years, the development of new therapeutic medicines has increasingly focused on the introduction of novel elements into drug molecules in order to improve their pharmacological properties. Sulfur (S) and phosphorus (P) have emerged as essential elements in several recently authorized medications due to their flexible chemical properties and different roles in biological systems[Citation1,Citation2]. Sulfur belongs to group 16 (also known as the oxygen group or chalcogens). Phosphorus belongs to group 15 (also known as the nitrogen group or pnictogens) on the periodic table. Nice reviews covered the approval of novel sulfur-containing drugs until year 2018 and 2019[Citation2,Citation3] and the approval of phosphorus till 2020[Citation1]. To investigate on the more recent approvals from year 2020, this review has been designed and prepared as a part of our ongoing interest in reviewing FDA approved medicines[Citation4–6]. Between 2020 and 2024, multiple FDA-approved medications containing sulfur or phosphorus entered the market, providing novel therapeutic options for a variety of pathological conditions such as infectious diseases, cancer, and metabolic disorders. Sulfur, a significant element in biological chemistry, can be found in a variety of amino acids and coenzymes, where it plays an important role in enzymatic and redox reactions.
Sulfur commonly exists in five different oxidation states, enabling it to enjoy a diversity of forms[Citation3]. Many medicinal substances and natural products contain sulfur-derived functional groups across a wide range of oxidation states (from −2 to +6). The primary functional weapons utilized in drug design and discovery are thioether, sulfoxide, sulfone, sulfonamide, sulfamate, sulfamide, and sulfur-related heterocycles. Organosulfur compounds make up almost 25% of all small-molecule medications in use in the period 2017–2020[Citation7]. Some examples of sulfur-containing drugs are shown in Figure 1: sulfonamides, sulfonylureas, thiazides and sulfoxides. Sulfonamides are a class of antibiotics that contain a sulfonamide group. Examples include: sulfamethoxazole (1) [often combined with trimethoprim (2)], used to treat bacterial infections like urinary tract infections and bronchitis[Citation8], sulfasalazine (3), used to treat inflammatory bowel diseases like ulcerative colitis and Crohn’s disease, and also for rheumatoid arthritis[Citation9].
Sulfonylureas are used to manage type 2 diabetes by increasing insulin release from the pancreas[Citation10]. Examples include: glipizide (4), glyburide (5) and glimepiride (6). Thiazides are a type of diuretic used to manage hypertension (high blood pressure) and edema[Citation11]. Examples include: hydrochlorothiazide (7), and clorothiazide (8). Among sulfoxides are esomeprazole (9, Nexium©) and omeprazole (10, Prilosec©) are worth to mention, both proton pump inhibitors that reduce stomach acid production. Recently, other sulfur-based moieties have received much attention in drug discovery. To name a couple, thioamides and sulfoximines. Thioamides, intriguing isosteres of amides, have received a lot of attention in drug development and medicinal chemistry programs, ranging from peptides to small molecule molecules[Citation12]. For example, elesclomol (11) (Figure 2) is an investigational drug that functions as a copper-transporting agent targeting mitochondria and initially discovered for the treatment of solid tumors[Citation13]. Sulfoximines are synthetically accessible and employed to treat multiple diseases bearing potential intellectual property advantages[Citation14]. For example, sulfoximine containing drugs BAY 1143572 (12) entered the clinic for the treatment of cancer[Citation15].
Phosphorus is generally considered to bear a 5+ oxidation state, but several lower redox states have been reported, including the toxic gas phosphine[Citation16]. Phosphorus is often included in drugs that involve phosphate groups or phosphonic acid derivatives. These compounds can act as prodrugs, increase water solubility, or enhance the drug stability or bioavailability. Selected examples include (Figure 3): bisphosphonates and nucleotide and nucleoside analogues.
Bisphosphonates are used to prevent bone resorption in conditions like osteoporosis and Paget’s disease[Citation17]. Examples include alendronate (13, Fosamax©), ibandronate (14, Boniva©), and zoledronic acid (15, Reclast©). Nucleotide and nucleoside analogs containing phosphate groups and used primarily as antiviral or anticancer agents[Citation18]. Examples include adefovir dipivoxil (16), used for the treatment of hepatitis B[Citation19] and tenofovir disoproxil fumarate (17) which is an antiretroviral used in HIV treatment[Citation20].
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Benedetto Tiz, D., Rosati, O., & Sancineto, L. (2025). Sulfur- and phosphorus-containing FDA approved drugs in the last five years (2020–2024): A journey among small molecules. Phosphorus, Sulfur, and Silicon and the Related Elements, 1–39. https://doi.org/10.1080/10426507.2025.2496521
