Synthesis of N-Substituted Benzamide Derivatives and their Evaluation as Antitumor Agents

Background: Histone deacetylases inhibitors (HDACIs) with different chemical structures have been reported to play an important role in the treatment of cancer. Objective: The study aims to modify the structure of Entinostat (MS-275) to discover new compounds with improved anti-proliferative activities and perform SAR studies on this class of bioactive compounds. Methods: Fourteen N-substituted benzamide derivatives were synthesized and their antiproliferative activities were tested with four cancer cell lines (MCF-7, A549, K562 and MDA-MB- 231) by MTT assay. Results: Compared with MS-275, six compounds exhibited comparable or even better antiproliferative activities against specific/certain cancer cell lines. Conclusion: The preliminary SARs showed that (ⅰ) the 2-substituent of the phenyl ring in the R group and heteroatoms of amide which can chelate with zinc ion are critical to the antiproliferative activity and (ⅱ) chlorine atom or nitro-group on the same benzene ring largely decreases their anti-proliferative activity. Molecular docking study illustrated the interaction (binding affinity) between the synthesized compounds and HDAC2 was observed to be similar to that of MS-275.

Role of halogen-involved intermolecular interactions and existence of isostructurality in the crystal packing of —CF3 and halogen (Cl or Br or I) substituted benzamides

A total of 23 benzamides are obtained through a simple reaction between chloro-/bromo-/iodoaniline and trifluoromethylbenzoyl chloride and characterized using single-crystal X-ray diffraction. Crystal structures of three series of benzamides based on N-chlorophenyl–trifluoromethyl–benzamide (nine compounds), N-bromophenyl–trifluoromethyl–benzamide (six compounds), and N-iodophenyl–trifluoromethyl–benzamide (eight compounds) are prepared to analyse the halogen-mediated noncovalent interactions. The influences of Cl/Br/I and trifluoromethyl substituents on the respective interactions are examined in the presence of a strong N—H...O hydrogen bond. This exercise has resulted in the documentation of frequently occurring supramolecular synthons involving halogen atoms in the crystal packing of benzamide molecules in the solid state. In the present study, a detailed quantitative evaluation has been performed on the nature, energetics, electrostatic contributions, and topological properties of short and directional intermolecular interactions derived from the electron density on halogenated benzamides in the solid state. Besides these, the occurrence of three-, two- and one-dimensional isostructurality in halogen (Cl or Br or I) substituted benzamide analogues is also investigated. A `region of co-existence' involving halogen-based intermolecular interactions in the vicinity of the sum of the van der Waals radii has been identified. Thus, the nature of the halogen (effective size), type of interaction and the packing characteristics via presence of additional interactions establish the subtle, yet important, role of cooperativity in intermolecular interactions in crystal packing.