Neglected tropical diseases caused by parasitic pathogens have caused an increase in research interest in drug discovery.

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Chagas disease is caused by Trypanosoma cruzi. Benznidazole and nifurtimox are drugs used for its therapy; nevertheless, they have collateral effects. NADH‐fumarate (FUM) reductase is a potential pharmacological target since it is essential for survival of parasite and is not found in humans. The objectives are to design and characterize the electronic structure of imidazole and nitroimidazole derivatives at DFT‐M06‐2X level in aqueous solution; also, to model the NADH‐FUM reductase and analyze its intermolecular interactions by molecular docking. Quantum‐chemical descriptors allowed to select the molecules with the best physicochemical properties and lowest toxicity. A high‐quality three‐dimensional structure of NADH‐FUM reductase was obtained by homology modeling. Water molecules do not have influence in the interaction between FUM and NADH‐FUM reductase. The main hydrogen‐binding interactions for FUM were identified in NADH, Lys172, and Arg89; while hydrophobic interactions in Phe479, Thr174, Met63. The molecules S3‐8, S2‐8, and S1‐8 could be inhibitors of NADH‐FUM reductase.

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