ANTIBACTERIAL

AGENTS

Dr. Noor M. Ali

 Silver and Mercury Salts -1
Silver and mercury salts have a long history of use as
antibacterial agents. The use of mercurochrome ((40),
Figure 1) as a topical disinfectant is now discouraged.
Silver sulfadiazine (38) finds use for treatment of
severe burns; the polymeric material slowly releases
.the antibacterial Ag ion
Silver nitrate is still used in many countries to prevent
ophthalmic disease in newborn children. The
mechanism of action of Ag and Hg is through slow
release of the active metal ion—inhibition of thiol
function in bacterial cell walls gives a rationale for the
.specificity of bactericidal action
Bismuth-containing Antiulcer Drugs -2

Bismuth compounds have been used for their antacid and

astringent properties in a variety of gastrointestinal disorders. The
effectiveness of bismuth is due to its bactericidal action against the
. Gram-negative bacterium, Helicobacter pylori
Usually the bismuth preparations are obtained by mixing an
inorganic salt with a sugar-like carrier (see Figure 2). Commonly
used agents are colloidal bismuth sub citrate (CBS), and bismuth
subsalicylate (BSS). The mechanism of action is complex and
includes inhibition of protein and cell wall synthesis, membrane
function, and ATP synthesis. The most notable salts are tripotassium
dicitratobismuth, bismuth salicylate, Pepto-Bismol (BSS), and De-Nol
(CBS; (41)). The ‘‘sub’’ designation most likely arose from
stoichiometric of oxygen to bismuth. The combination of ranitidine
(a histamine H2-receptor antagonist) and bismuth citrate is
marketed as Ranitidine Bismutrex for the management of peptic
. ulcer and ulcers associated with H. pylori
Much progress has been made on the coordination
chemistry of these preparations. Detailed molecular
characterization is obviously of primary importance in
understanding chemical and biochemical function. Bi III is
highly acidic in aqueous medium and the oxygen-rich nature of
the sugar carrier ligands leads to formation of di- and
Polynuclear-bridged complexes, based on the typical binuclear
unit (41) shown in Figure 2. The nature of the
ranitidine/bismuth citrate adduct has been examined and
second coordination sphere effects were noted for the organic
amine. Methylthiosalicylate has also been used instead of
salicylate, and discrete complexes (e.g., (42)) have been
comprehensively characterized. Bismuth (III) remarkably forms
stable complexes with GSH and transferrin. The latter
observation may be correlated with the high acidity of the Bi
.III ion
 Metal-containing Drugs as Antiparasitic Agents -3
There remains an urgent need for new effective antiparasitic
agents, an area of drug development that has languished because
of poor economic return. The spread of resistance to chloroquine
(an antimalaria treatment) is one reason for attention to be paid
to this area, as well as the sheer numbers of people affected.
Antimony compounds (43) and (44) (Figure 3) are used to treat
leishmaniasis (H. Sun, personal communication). Another
approach is to complex metal ions to known antiparasitic agents
in attempts to gain selective uptake or selective action of the
metal– drug conjugate. Gold and ruthenium complexes of
chloroquine and clotrimazole have been described (45) and (46),
Figure 3 In favorable cases, some of these compounds show good
activity—the chloroquine complexes being useful even in
. chloroquine-resistant cases
PHARMACODYNAMIC
USES OF METAL
COMPLEX DRUGS
 Lithium Carbonate -1

The clinical value of lithium has been recognized since

1949. Lithium carbonate is used in manicm depressive
psychoses for the treatment of recurrent mood changes.
Mood stability may only occur after months rather than
weeks. The drug is administered orally in doses up to 2 g
day1 (30mmol day1). The serum Li concentration should be
The development of lithium-specific electrodes has assisted
greatly in monitoring patient compliance. The toxicity profile
of lithium carbonate is now well established and the drug is
safely administered and well tolerated. It is of limited use in
other psychiatric disorders such as pathological aggression,
although additional benefit may also include a reduction in
.actual or attempted suicide in the range of 0.4–0.8mmol lL
 Vanadium Complexes in Diabetes-2
The role of vanadium in biological systems in general is of
increasing interest. The discovery of the insulin-like properties of
vanadate ions spurred research into the clinical use of vanadium
compounds as insulin mimics. Inadequate glucose metabolism,
either through absence of endogenously secreted insulin or
insulin resistance, leads to diabetes mellitus. The potential of
insulin-mimetic compounds as drugs lies in their oral
administration—insulin, as a small protein, is not orally active.
The vanadate (V) ion is effective upon oral administration, and an
obvious strategy to enhance the pharmacokinetic characteristics
and the efficacy of the insulin-mimetic response is complexation
.of vanadate with suitable biologically compatible ligands
Insulin binding to the extracellular side of cell membranes
initiates the ‘‘insulin cascade’’, a series of
. phosphorylation/dephosphorylation steps
A postulated mechanism for vanadium is substitution of
vanadate for phosphate in the transition state structure of protein
tyrosine phosphetase (PTP). In normal physiological conditions, the
attainable oxidation states of vanadium are VIII, VIV and VV.
Relevant species in solution are vanadate, (a mixture of HVO4
H2VO4) and vandal VO2 Vandal is not a strong inhibitor of PTPs,
suggesting other potential mechanisms for insulin mimesis for this
cation. Both VIV and VV coordination compounds have been tested
as insulin mimics. The preponderance of VIV compounds contain
the V¼O(L-L)2 motif (e.g., (47) and (48), and complexes containing
a variety of O,O; N,O; N,S; and S,S bidentate ligands L–L have been
synthesized and tested. Control of liability and ligand displacement
are important criteria for drug design in terms of delivery of the
biologically active vanadate. Clinical trials have focused to date on
sodium ortho vanadate and the bis(maltolato)oxovanadium(IV)
.compound (BMOV) (47)
Gold Compounds as Antiarthritic Agents -3

Gold salts have had a long history of use in rheumatoid

arthritis. The development of orally active auranofin (also
known as Rid aura; (49,50), Figure 4) was a major
improvement over the early ‘‘inject able gold’’ preparations
which were polymeric (e.g., (51)–(53)). However, use has
declined with the popularity of no steroidal anti inflammatory
drugs (NSAIDS) such as indomethacin; a recent estimate of the
commercial value for auranofin was $6 million. The
mechanism of action is postulated to occur through thiolate
. exchange reactions
The structures of the polymeric gold compounds have been
described in detail. An interesting feature of gold metabolism
is the production of [Au(CN)2] as a metabolite of the gold-thiol
compounds
Nitric Oxide in Physiology and Medicine -4

An intriguing aspect of the role of metal complexes in medicine

is the role of NO. The nitroprusside ion, [Fe(NO)(CN)5]2 is a
vasodilator used in emergency situations to treat hypertensive
patients in operating theaters. The complex is 30–100 times
more potent than simple nitrites. The mechanism is considered
to be release of NO, an understanding prompted by the
emergence of NO as a prominent cell signaling molecule. Related
to the biology of NO is production of peroxynitrite ONOO
through reaction of NO with O2. In this regard, production of
peroxynitrite may play a role in many pathological conditions.
Water-soluble porphyrins and texaphyrins may catalytically react
with ONOO and may have clinical utility in peroxynitrite
.Scavenging
Lanthanum Carbonate -5

Patients with end-stage renal disease hyperphosphatemia

ineffectively filter excess phosphate that enters the body in
the normal diet. Elevated phosphate produces the bone
disorder renal osteodystrophy. Skeletal deformity may occur,
.possibly associated with cardiovascular disease
Calcium deposits may further build up around the body and
in blood vessels creating further health risks. The use of
lanthanum carbonate is being promoted as an alternative to
aluminum based therapies. Systemic absorption, and cost
have produced a clinical candidate, Fosrenol (AnorMED), an
.intriguing use of a lanthanide compound in therapy