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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