Design, synthesis, and molecular docking of new phenothiazine incorporated N-Mannich bases as promising antimicrobial agents

Abstract

The present work aims to synthesize four series of phenothiazine incorporation Mannich bases. Therefore, 10-methyl-10H-phenothiazine-3-sulfonamide <b>(4)</b> which was subjected to react with some secondary amines and formaldehyde to give the Mannich bases <b>5a-f</b>, and <b>6</b>-<b>13</b>. Compound <b>13</b> was then subjected to react with some secondary amines and formaldehyde to give the corresponding Mannich bases <b>14a-f</b>. In total, twenty-two new compounds were synthesized and evaluated for <i>in vitro</i> growth inhibition activity against <i>P. aeruginosa</i>, <i>E. coli</i>, and <i>S. aureus</i>. Among the tested compounds, compounds <b>3</b>, <b>5a</b>, <b>5c</b>, <b>6</b>, <b>12</b>, <b>13</b>, <b>14d</b>, and <b>14e</b> exhibited good activity with a MIC value (12.5 μg/mL), compounds <b>5b</b>, <b>10</b>, <b>11</b>, <b>14a</b>, and <b>14c</b> exhibited strong activity against the growth of <i>S. aureus</i> with a MIC value (6.25 μg/mL), and compound <b>14b</b> superior against <i>S. aureus</i> with a MIC value (3.125 μg/mL) compared to drug reference ciprofloxacin with MIC value (2 μg/mL). The molecular docking investigation revealed the presence of many derivatives with high binding affinities and distinct interaction patterns with the target protein. Derivatives <b>14a-e</b> emerged as the most promising possibilities, displaying the greatest binding energies and a varied variety of interaction types, including hydrogen bonding and pi interactions, over different distances, with derivative <b>14b</b> exhibiting the highest binding energy at S = -8.3093 kcal/mol. These derivatives displayed superior binding affinities and various interaction mechanisms with the target protein, suggesting that they have great promise as lead compounds for future development into therapeutic medicines.