Chemical Properties
Orange Solid
Uses
Antiprotozoal (Trypanosoma)
Uses
Antiprotozoal. Showing anti-Trypanosoma cruzi activity.
Description
Nifurtimox is manufactured by Bayer and marketed under the trade name Lampits.It is a nitrofuran derivative that was developed specifically for the treatment of American trypanosomiasis (Chagas'disease) (Packachanian, 1957). Nifurtimox is one of two drugs approved for use in treatment of Chagasdisease. It was shown to be the most active and least toxic of this group of agents in preclinical studies and was evaluated in clinical trials in the 1960s and subsequently marketed for use in Chagas’ disease in Latin America in the late 1960s and early 1970s. Although the use of nifurtimox for Chagas’ disease has decreased with the availability of benznidazole, a potentially more active and less toxic agent, there has been a resurgence of interest in and use of nifurtimox for the treatment of second-stage human African trypanosomiasis (HAT)caused by Trypanosoma brucei gambiense.
Definition
ChEBI: Nifurtimox is a nitrofuran antibiotic.
General Description
Nifurtimox acts as a hypoxia-activated cytotoxin, which specifically kills clonogenic tumor cells under hypoxic conditions. It is used to treat Chagas disease and African trypanosomiasis. Nifurtimox inhibits neuroblastoma and medulloblastoma cell growth.
Pharmaceutical Applications
A water-soluble synthetic compound available for oral use. It
exhibits antibacterial activity typical of the group, but its most
notable property is its activity against trypanosomes, especially
Trypanosoma cruzi.
A plasma concentration of 0.5–1 mg/L is achieved c. 2 h
after an oral dose of 15 mg/kg. The plasma half-life is 2–4 h. In
common with other nitrofurans, it is rapidly and extensively
metabolized, so that less than 1% of a dose is excreted intact
in the urine. In renal failure, clearance is somewhat reduced
but the half-life is unchanged.
Adverse events are common. Many patients experience
anorexia, which may be combined with vomiting and abdominal
pain. There may also be neurological reactions such as restlessness,
insomnia, headache and disorientation.
It is used in the treatment of Chagas disease (South
American trypanosomiasis). It has also found some use in the
treatment of African sleeping sickness in combination with
eflornithine.
Biochem/physiol Actions
Nifurtimox is a nitrofurane derivative used to treat diseases caused by trypanosomes. Nifurtimox was discovered empirically and its mechanism of action is unclear. It is believed that nifurtimox exerts its biological activity through the bioreduction of the nitro-group to a nitro-anion radical which undergoes redox-cycling with molecular oxygen.
Mechanism of action
The drug is given orally and is well absorbed from
the gastrointestinal tract. It is rapidly metabolized, and
only low levels are found in blood and tissues.The drug
is excreted in the urine, primarily in the form of
metabolites.
Clinical Use
Nifurtimox is trypanocidal and exerts an effect on
the trypomastigote and amastigote forms of T. cruzi. It
is effective in the treatment of the acute form of
Chagas’ disease but is less effective once the disease becomes
chronic. The drug is moderately well tolerated,
and treatment generally lasts 3 to 4 months. Cure rates
of 80 to 90% have been reported. Since much of the tissue
damage caused by the disease is irreversible, early
diagnosis and treatment are important. Nifurtimox has
also been used in T. gambiense infection with meningoencephalopathic involvement.
Synthesis
Nifurtimox, 1,1-dioxide 4-[(5-nitrofuryliden)amino]-3-methylthiomorpholine
(37.4.7), is made by the following scheme. Interaction of 2-mercaptoethanol with propylene
oxide in the presence of potassium hydroxide gives (2-hydroxyethyl)-(2-hydroxypropylsulfide) (37.4.3), which undergoes intramolecular dehydration using potassium bisulfate to
make 2-methyl-1,4-oxithiane (37.4.4). Oxidation of this using hydrogen peroxide gives
2-methyl-1,4-oxithian-4,4-dioxide (37.4.5), which when reacted with hydrazine transforms
to 4-amino-3-methyltetrahydro-1,4-thiazin-1,1-dioxide (37.4.6). Reacting this with 5-nitrofurfurol gives the corresponding hydrazone?athe desired nifurtimox.
