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.

Head group analogues of the antibacterial and antiparasitic drug Nitazoxanide (NTZ) are presented. A library of 39 analogues was synthesized and assayed for their ability to suppress growth of Helicobacter pylori, Campylobacter jejuni, Clostridium difficile and inhibit NTZ target pyruvate:ferredoxin oxidoreductase (PFOR). Two head groups assayed recapitulated NTZ activity and possessed improved activity over their 2-amino-5-nitrothiazole counterparts, demonstrating that head group modification is a viable route for the synthesis of NTZ-related antibacterial analogues.Nitazoxanide 1 (NTZ - Fig. 1) is a broad-spectrum FDA approved drug utilized for the treatment of anaerobic intestinal parasites Giardia lamblia and Cryptosporidium parvum but is efficacious in the treatment of other anaerobic bacteria and parasites residing in the human gut. [1][2][3][4] NTZ has also been shown to have activity against microbial biofilms, rotavirus, influenza A/B/H I N 1 , hepatitis B/C and Mycobacterium tuberculosis. [5][6][7][8][9][10] Although structurally similar to other nitro-drugs like metronidazole 2 (Fig. 1), the 5-nitro group on the thiazole ring of NTZ is not metabolically reduced. As a result, nitro reduction is not responsible for NTZ activity as is the case for most nitro-containing drugs. 3,11,12 Resistance to NTZ has not been observed clinically or through in vitro generation methods which further supports a different mechanism of action (MoA). 13 The MoA for NTZ has been elucidated to occur through the anion of NTZ. The NTZ anion abstracts a proton from the thiamine pyrophosphate vitamin cofactor of the essential enzyme pyruvate:ferredoxin oxidoreductase (PFOR), thereby inhibiting production of acetylCoenzyme A and CO 2 necessary for energy metabolism. 14, 15 PFOR is present in all strictly anaerobic bacteria, anaerobic parasites and ε-proteobacteria (Helicobacter pylori and Campylobacter jejuni), while mammals and eubacteria oxidize pyruvate by the NTZ insensitive pyruvate dehydrogenase (PDH) (Fig. 2). 14-19 Therefore, PFOR of H. pylori, C. © 2010 Elsevier Ltd. All rights reserved. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. jejuni, and Clostridium difficile is a logical small-molecule drug target and we postulated that modification of the 2-amino-5-nitrothiazole portion of NTZ would potentiate analogue activity. SupplementaryThe key interaction responsible for biological activity is believed to occur between NTZ and the TPP vitamin co-factor (Fig. 3). 14 NTZ was shown to completely prevent the production of both acetyl-CoA and CO 2 indicating that inhibition oc...

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