:
Leflunomide (LFM) and its active metabolite, teriflunomide (TFM), have drawn a lot
of attention for their anticancer activities, treatment of rheumatoid arthritis and malaria due to
their capability to inhibit dihydroorotate dehydrogenase (DHODH) and Plasmodium falciparum
dihydroorotate dehydrogenase (PfDHODH) enzyme. In this investigation, the strength of
intramolecular hydrogen bond (IHB) in five analogs of TFM (ATFM) has been 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 has
been 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 has been studied by natural bond
orbital analysis (NBO). 1H NMR calculations show an upward trend in the proton chemical shift
of the enolic proton in the chelated ring (14.5 to 15.7ppm) by increasing the IHB strength. All
the calculations confirmed the strongest IHB in 5-F-ATFM and the weakest IHB in 2-F-ATFM.
Molecular orbital analysis, including the HOMO-LUMO gap and chemical hardness, was
performed to compare the reactivity of inhibitors. Finally, molecular docking analysis was
carried out to identify the potency of inhibition of these compounds against PfDHODH enzyme.