Nitoxin Nitazoxanide The activity of ..
Physicochemical characterization of two new Nitazoxanide analogs with antiparasitic activity
anisomycin and some other inhibitors of eukaryotic protein synthesis.
In 1996, Dubreuil et al reported that nitazoxanide and its circulating metabolite, tizoxanide, were active against a broad range of obligate and facultative Gram-positive and Gram-negative anaerobic bacteria, and in 1998, Mégraud et al. reported that the two compounds were also active against Helicobacter pylori (Dubreuil et al., 1976; Mégraud et al., 1998).
Nitazoxanide was originally synthesized by Rossignol in 1973 at the Radium Institute where he studied synthetic organic chemistry for his doctorate degree at the University of Paris, also known in those days as La Sorbonne. Raymond Cavier, a Professor of Parasitology in the Parasitology Laboratory at the Faculty of Pharmacy of the University of Paris tested nitazoxanide against a broad range of parasites (Rossignol & Cavier, 1975; Cavier & Rossignol, 1982).
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In 2006, Rossignol et al. reported the activity of nitazoxanide and tizoxanide in cell culture assays and studies were conducted evaluating nitazoxanide in the treatment of diarrhea caused by rotavirus and norovirus in adults and children (Rossignol et al., 2006; Rossignol & El-Gohary, 2006). In 2008, Korba et al. reported the activity of nitazoxanide and tizoxanide against hepatitis B and C in cell culture assays, and in 2009 Rossignol et al reported studies evaluating nitazoxanide combined with pegylated-interferon and ribavirin in the treatment of chronic hepatitis C genotype 4 in adult patients (Korba et al., 2008; Rossignol et al., 2009). In 2009, Rossignol et al. reported in vitro activity of nitazoxanide and tizoxanide against influenza viruses (Rossignol et al., 2009).
While pursuing development work with nitazoxanide, Rossignol and Andrew Stachulski in the United Kingdom at the University of Liverpool Department of Chemistry initiated a drug discovery program in 2000 that focused on synthesis of new derivatives of nitazoxanide. More than 300 chemical compounds were prepared using the scaffold of nitazoxanide, two of them being in preclinical development as broad-spectrum antivirals. Preclinical research is typically performed for Romark under contract with specialty laboratories in academia or contract research organizations. Romark medical personnel are active in directing the company’s clinical development programs.
Artesunate (AS) is a medication used to treat malaria
Dubreuil, L., Houcke, I., Mouton, Y. & Rossignol, J.F. In vitro Evaluation of Activities of Nitazoxanide and Tizoxanide against Anaerobes and Aerobic Organisms. Antimicrobial Agents and Chemotherapy. 1996; 40: 2266-2270.
NITAZ is a synthetic antiprotozoal agent and is well absorbed from GIT. The antiprotozoal activity of Nitazoxanide is believed to be due to interference with the pyruvate ferredoxin oxidoreductase (PFOR) enzyme dependent electron transfer reaction which is essential to anaerobic energy metabolism. Following oral administration in human, Nitazoxanide is rapidly hydrolyzed to an active metabolite, tizoxanide (deacylated-Nitazoxanide), which is readily reduced by PFOR enzymes from the parasites by transfer of electrons. This reduced form of Nitazoxanide deprives parasite of their energy and eradicates them from the body.
The intravenous form is preferred to quinidine for severe malaria
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Giardia lamblia (also known as Giardia duodenalis or Giardia intestinalis) is a flagellated protozoan parasite 
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Diarrhea Medication: Antibiotic and antiparasitics …
A library composed of Nitazoxanide-based analogues was synthesized and assayed for increased antibacterial efficacy against the pyruvate:ferredoxin oxidoreductase (PFOR) utilizing microorganisms Helicobacter pylori, Campylobacter jejuni and Clostridium difficile. Derivatives were found to recapitulate and improve activity against these organisms and select analogues were tested for their ability to disrupt the PFOR enzyme directly. The library was also screened for activity against staphylococci and resulted in the identification of analogues capable of inhibiting both staphylococci and all PFOR organisms at low μM MIC concentrations with low toxicity to human foreskin cells.
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NTZ is a unique member of the nitro-drug family (). Unlike most nitro drugs,[, , ] the 5-nitro group of NTZ is metabolically stable and is not reduced as part of the mechanism of action (MoA). Although nitro group containing drugs and analogues are seldom pursued in a drug discovery program due to mutagenic and potentially toxic side effects, NTZ’s stability and lack of nitro reduction make it an important exception.
Norovirus Gastroenteritis in Immunocompromised Patients …
Most of the library members selected and tested retained nearly equipotent inhibitory activity against the PFOR enzyme compared to NTZ but failed to significantly show increased efficacy at the enzymatic target to correlate the increase in activity against PFOR utilizing organisms. Of note are the relatively low PFOR inhibition values for analogues 23, 41 and 61 yet the potent values for inhibition against H. pylori, C. jejuni and to some extent, C. difficile. PFOR results were also complicated by a complex pattern of differing rates that occurred during the PFOR assay which indicated that some activity may be attributable to a nitroreduction mechanism. Experiments to delineate the differences in PFOR activity versus antibacterial assays and the possible role of nitroreduction in the MoA are currently being investigated.
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