( 2Z )-3-Hydroxy-3-(4-R-Phenyl)-Prop-2-Enedithioic Acids as New Antituberculosis Compounds

Tuberculosis is an infectious disease caused by the bacillus . Compounds including a sulfur-containing scaffold have been shown to be key scaffolds in various antituberculosis agents. Interestingly, the 3-hydroxy-3-phenyl-prop-2-enedithioic acids have, to the best of our knowledge, not been previously described as antituberculosis agents. In the present study, we investigated the role of substituents attached to the phenyl ring of a 3-hydroxy-3-phenyl-prop-2-enedithioic acid scaffold (compounds ) in inhibiting the growth of strain H37Rv. (Z)-3-hydroxy-3-(4-R-phenyl)-prop-2-enedithioic acids , with R groups including various electron-donating or electron-withdrawing groups, were designed by structurally modifying the lead compound . The syntheses of involved each one-step procedure starting from the corresponding substituted acetophenone. Compounds were tested against strain H37Rv to evaluate their bacterial growth inhibitory activities. ADMET profiles were predicted by employing three different methods. In addition, molecular docking studies were carried out, based on the molecular similarities of the synthesized compounds with ethionamide ( ), on the active site of the H37Rv (3R)-hydroxyacyl-ACP (HadAB) dehydratase heterodimer. The antituberculosis activities of compounds could be explained in terms of the presence of electron-donating or electron-withdrawing substituents on the aromatic ring of the substituted 3-hydroxy-3-phenyl)-prop-2-enedithioic acid core. The activity and selectivity index (SI) value of ( )-3-hydroxy-3-(4-nitrophenyl)-prop-2-enedithioic acid suggested that this compound could be used for the design of novel antituberculosis agents. Most of the synthesized molecules showed an acceptable ADME profile and a low probability of being toxic. Docking studies of and showed them forming hydrogen bonds with the ACys61 residue of the HadAB enzyme. Our results suggested that the antituberculosis compound could be used for the design of novel antituberculosis agents.