Improved Syntheses, Crystal Structures Analysis, DFT Calculation, Anticancer and Antibacterial Properties of Some 4-(Benzylamino)benzoic Acid Derivatives

A series of 4-(benzylamino)-benzoic acid derivatives ArCH₂NH-4-C₆H₄CO₂H (<b>1-19</b>) (Ar = C₆H₅ (<b>1</b>); 4-Cl-C₆H₄ (<b>2</b>); 4-NMe-C₆H₄ (<b>3</b>); 4-Br-C₆H₄ (<b>4</b>); 3-NO₂-C₆H₄ (<b>5</b>); 4-NO₂-C₆H₄ (<b>6</b>); 2-OMe-C₆H₄ (<b>7</b>); 3-OMe-C₆H₄ (<b>8</b>); 4-OMe-C₆H₄ (<b>9</b>); 2,3-OMe-C₆H₃ (<b>10</b>); 3,4-OMe-C₆H₃ (<b>11</b>); 2-OH, 3-OMe-C₆H₃ (<b>12</b>); 3-OMe, 4-OH-C₆H₃ (<b>13</b>); 3,5-OMe, 4-OH-C₆H₄ (<b>14</b>); 2-OH-5-Br-C₆H₃ (<b>15</b>), 3-OH-C₆H₄ (<b>16</b>); 4-SMe-C₆H₄ (<b>17</b>); 2,3-OH-C₆H₃ (<b>18</b>); 3-CF₃-C₆H₄ (<b>19</b>)) were synthesized via reductive amination of <i>p</i>-aminobenzoic acid with substituted benzaldehydes and sodium borohydride. The structures were confirmed by MS, FT-IR, NMR, and E.A., with single-crystal X-ray diffraction elucidating key intermolecular interactions in compounds <b>2</b>, <b>4</b>, <b>7</b>-<b>9</b> and <b>11</b>. Hirshfeld surface analysis and 2D fingerprint plots highlighted noncovalent interactions contributing to crystal packing. DFT calculations (PBE0/def2-TZVP/CPCM) provided optimized geometries, HOMO-LUMO gaps, and electrostatic surface potentials. TD-DFT simulations supported experimental UV-vis spectra. Several derivatives (<b>2</b>, <b>3</b>, <b>5</b>, <b>7</b>, <b>8</b>, <b>10</b>, <b>11</b>, <b>13-16</b>) showed moderate antibacterial activity (MIC = 64-128 μg/mL) against different strains of bacteria, while compound <b>18</b> exhibited promising anticancer activity with IC₅₀ values of 90.69 μM against Non-Small Cell Lung Cancer cell line (A549) and 32.22 μM against Small Cell Lung Cancer cell line (H69).