Sulfaguanidine Hybrid with Some New Pyridine-2-One Derivatives: Design, Synthesis, and Antimicrobial Activity against Multidrug-Resistant Bacteria as Dual DNA Gyrase and DHFR Inhibitors

Abstract

Herein, a series of novel hybrid sulfaguanidine moieties, bearing 2-cyanoacrylamide <b>2a</b>-<b>d</b>, pyridine-2-one <b>3</b>-<b>10</b>, and 2-imino-2<i>H</i>-chromene-3-carboxamide <b>11</b>, <b>12</b> derivatives, were synthesized, and their structure confirmed by spectral data and elemental analysis. All the synthesized compounds showed moderate to good antimicrobial activity against eight pathogens. The most promising six derivatives, <b>2a</b>, <b>2b</b>, <b>2d</b>, <b>3a</b>, <b>8</b>, and <b>11</b>, revealed to be best in inhibiting bacterial and fungal growth, thus showing bactericidal and fungicidal activity. These derivatives exhibited moderate to potent inhibition against DNA gyrase and DHFR enzymes, with three derivatives <b>2d</b>, <b>3a</b>, and <b>2a</b> demonstrating inhibition of DNA gyrase, with IC₅₀ values of 18.17-23.87 µM, and of DHFR, with IC₅₀ values of 4.33-5.54 µM; their potency is near to that of the positive controls. Further, the six derivatives exhibited immunomodulatory potential and three derivatives, <b>2d</b>, <b>8</b>, and <b>11</b>, were selected for further study and displayed an increase in spleen and thymus weight and enhanced the activation of CD4⁺ and CD8⁺ T lymphocytes. Finally, molecular docking and some AMED studies were performed.