Antimony and Bismuth

Antimony and bismuth have been applied in medicine for centuries due to their antiparasitic and antibacterial properties. Sb(III) and Bi(III) are borderline metal ions and exhibit a high affinity for oxygen, nitrogen, and sulfur. Unlike Sb, where the +5 oxidation state is favored, the +3 oxidation state is the most common and stable form of Bi.

Millions of people suffering from "leishmaniasis" worldwide, particularly in the developing countries, are subject to intravenous treatment with drug formulations of pentavalent antimony, Sb(V) complexes with polyhydroxy carbohydrate ligands. Very limited resources have been invested by the developed world in optimizing these drugs. Thus, at the moment, patients infected with the parasites Leishmania spp. undergo long treatments with extremely high "nontarget" doses of Sb, which often result in severe side effects. Although, alternative antileishmania drugs are available in the market, or are in the development phase, antimony-based drugs have remained the main treatment worldwide since the 1930s (except for certain domains where resistance has curbed their use).

Sodium stibogluconate (Pentostam) and meglumine antimonate (Glucantime) are the two drugs in current use and typically administered intravenously. The carbohydrate ligands in Pentostam and Glucantime, gluconic acid, and N-methyl-D-glucamine, respectively, increase the general solubility of antimony and may serve to deliver Sb to the macrophages, where the protozoa that cause "leishmaniasis" undergo division.

Pentostam and Glucantime [both based on Sb(V)] are believed to be only prodrugs and Sb(III) accounts for the active form of antimony at the target site. Antimony(III) possesses higher antileishmania activity than Sb(V), but due to its higher toxicity it has no direct therapeutic use. Trypanothione, the most abundant low molecular weight thiol-containing ligand in the parasites (while nonexisting in human) may act as the reductant in the parasites. Once Sb(III) is present in the parasite it can interfere with several enzymes and proteins, which eventually destroys the parasite.

Although bismuth preparations have historically been applied in the treatment of a number of diseases, including syphilis and hypertension, their application during the last decades has been

FIGURE 10.16 Bismuth antiulcer complex. Suggested structure of a binuclear bismuth(III) complex with citrate. The Bi atoms are orange while oxygen is red and carbon black. The complex may form larger clusters with bridging citrate anions.

restricted to gastrointestinal therapy. Since the 1970s, two Bi(III) compounds have been most commonly used worldwide; bismuth subsalicylate (BSS) for the prevention and treatment of diarrhea and dyspepsia, and colloidal bismuth subcitrate (CBS; Figure 10.16) for the treatment of peptic ulcers. Most ulcers are associated with the bacterium, Helicobacter pylori. In the 1990s, a new Bi(III)-containing drug was developed, ranitidine bismuth citrate (RBC), which combines the antisecretory action of ranitidine with the bactericidal properties of bismuth. Although the use of bismuth containing drugs for years was declining, they are now again becoming increasingly popular as combination pharmaceuticals due to developed antibiotics resistance by H. pylori.

All bismuth(III) drugs are chelates of complicated polymeric nature. In BSS, salicylate ligands coordinate to bismuth atoms via chelation, with extraordinary variations in binding modes. In CBS, Bi(III) is aggregated through citrate bridges and H-bonds to form complex polymers. The actual structure determination of bismuth-based drugs is complicated by the ability of the drugs to change composition with pH and concentration.

The exact reaction mechanism of Bi(III) drugs is not fully understood, but the therapeutic activity may result from mucosa-protective properties and from degradation of H. pylori. There is no doubt that Bi(III) possesses antimicrobial activity itself and not only its organic ligand as was once believed. The major target for Bi(III) appears to be proteins and enzymes. Pathogenic microorganisms such as H. pylori produce large amounts of enzymes, and Bi(III) inhibits several of these enzymes, including alcohol dehydrogenase (ADH) and urease. The inhibition of ADH is likely due to the displacement of Zn(II) by Bi(III) at the active site since Bi(III) has higher affinity for thiolate groups than Zn(II). Urease has long been regarded as a potential target for bismuth-based drugs, as the enzyme catalyzes the degradation of urea into carbon dioxide and ammonia, which helps to neutralize the acidic environment in order for the bacteria to survive the hostile environment. Presumably, Bi(III) binds to exposed thiolates of the enzyme and blocks the entrance to the active cavity of the enzyme.

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