In this investigation, the strength of intramolecular hydrogen bond (IHB) in five analogs of TFM (ATFM) was analyzed employing density functional theory (DFT) using B3LYP/6-311++G (d, p) level and molecular orbital analysis in the gas phase and water solution. 
B3LYP/6-311++G (d, p)
Effect of the Intramolecular Hydrogen Bond on the Active Metabolite Analogs of Leflunomide for Blocking the Plasmodium falciparum Dihydroorotate Dehydrogenase Enzyme: QTAIM, NBO, and Docking Study.BACKGROUND
 A detailed electronic structure study was performed using the quantum theory of atoms in molecules (QTAIM) and the hydrogen bond energies (EHB) of stable conformer obtained in the range of 76-97 kJ/mol, as a medium hydrogen bond.  At first, intramolecular hydrogen bonds in five ATFMs were evaluated by the DFT method, quantum theory of atoms in molecules (QTAIM), nuclear magnetic resonance (NMR), natural bond orbital (NBO), and molecular orbital (MO) analyses.  All the computed results confirm the following trend in the intramolecular hydrogen bond strength in five mono-halo-substituted 2-cyano-3-hydroxy-N-phenylbut-2-enamide (ATFM): 5-FATFM> 4-Br-ATFM ≈ 3-Br-ATFM>3-Cl-ATFM>TFM-Z>2-F-ATFM which is in agreement with QTAIM, NMR, and NBO results. 
QTAIM
Effect of the Intramolecular Hydrogen Bond on the Active Metabolite Analogs of Leflunomide for Blocking the Plasmodium falciparum Dihydroorotate Dehydrogenase Enzyme: QTAIM, NBO, and Docking Study.BACKGROUND
 In this investigation, the strength of intramolecular hydrogen bond (IHB) in five analogs of TFM (ATFM) was analyzed employing density functional theory (DFT) using B3LYP/6-311++G (d, p) level and molecular orbital analysis in the gas phase and water solution.  A detailed electronic structure study was performed using the quantum theory of atoms in molecules (QTAIM) and the hydrogen bond energies (EHB) of stable conformer obtained in the range of 76-97 kJ/mol, as a medium hydrogen bond.  The effect of substitution on the IHB nature was studied by natural bond orbital analysis (NBO).  Hydrogen bonds play a key role in the interaction between drugs and enzymes.


 The aim of the present work is to investigate the effect of the strength of intramolecular hydrogen bonds (IHBs) in the active metabolite analogs of leflunomide or analogs of teriflunomide (ATFMs) and study the interaction of these inhibitors against the PfDHODH enzyme using quantum mechanical methods.


 At first, intramolecular hydrogen bonds in five ATFMs were evaluated by the DFT method, quantum theory of atoms in molecules (QTAIM), nuclear magnetic resonance (NMR), natural bond orbital (NBO), and molecular orbital (MO) analyses.  All the computed results confirm the following trend in the intramolecular hydrogen bond strength in five mono-halo-substituted 2-cyano-3-hydroxy-N-phenylbut-2-enamide (ATFM): 5-FATFM> 4-Br-ATFM ≈ 3-Br-ATFM>3-Cl-ATFM>TFM-Z>2-F-ATFM which is in agreement with QTAIM, NMR, and NBO results. 
NBO
Effect of the Intramolecular Hydrogen Bond on the Active Metabolite Analogs of Leflunomide for Blocking the Plasmodium falciparum Dihydroorotate Dehydrogenase Enzyme: QTAIM, NBO, and Docking Study.BACKGROUND
 Then, the interaction of these inhibitors against the PfDHODH enzyme were compared using molecular docking study.


 Also, the docking study revealed maximum binding energy between TFM-Z and PfDHODH enzyme.
Docking Study