Antiprotozoal Nitazoxanide Derivatives: Synthesis, Bioassays and QSAR Study Combined with Docking for Mechanistic Insight

• Published in: Current computer-aided drug design Vol. 11; no. 1; p. 21
• Main Authors: Scior, Thomas, Lozano-Aponte, Jorge, Ajmani, Subhash, Hernández-Montero, Eduardo, Chávez-Silva, Fabiola, Hernández-Núñez, Emanuel, Moo-Puc, Rosa, Fraguela-Collar, Andres, Navarrete-Vázquez, Gabriel
• Format: Journal Article
• Language: English
• Published: United Arab Emirates 01.07.2015
• Subjects: Antiprotozoal Agents - chemistry; Antiprotozoal Agents - pharmacology; Entamoeba histolytica - drug effects; Entamoeba histolytica - enzymology; Entamoebiasis - drug therapy; Entamoebiasis - parasitology; Humans; Molecular Docking Simulation; Pyruvate Synthase - antagonists & inhibitors; Pyruvate Synthase - metabolism; Quantitative Structure-Activity Relationship; Thiazoles - chemistry; Thiazoles - pharmacology
• ISSN: 1875-6697
• DOI: 10.2174/1573409911666150414145937

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.