Antiprotozoal Nitazoxanide Derivatives: Synthesis, Bioassays and QSAR Study Combined with Docking for Mechanistic Insight
In view of the serious health problems concerning infectious diseases in heavily populated areas, we followed
the strategy of lead compound diversification to evaluate the near-by chemical space for new organic compounds. To this
end, twenty derivatives of nitazoxanide (NTZ) were synthesized and tested for activity against Entamoeba histolytica
parasites. To ensure drug-likeliness and activity relatedness of the new compounds, the synthetic work was assisted by a
quantitative structure-activity relationships study (QSAR). Many of the inherent downsides – well-known to QSAR
practitioners – we circumvented thanks to workarounds which we proposed in prior QSAR publication. To gain further
mechanistic insight on a molecular level, ligand-enzyme docking simulations were carried out since NTZ is known to
inhibit the protozoal pyruvate ferredoxin oxidoreductase (PFOR) enzyme as its biomolecular target.
Keywords: 3D-QSAR, 4D-QSAR, 5D-QSAR, mathematical regularization, nitrothiazole, PFOR, QSAR pitfalls, tizoxanide.
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