Design and Synthesis of Hybrid Compounds for Potential Treatment of Bacterial Co-Infections: In Vitro Antibacterial and In Silico Studies

<b>Background:</b> The need for innovative therapeutic strategies to enhance patient outcomes has increased due to the rise in bacterial co-infections associated with COVID-19. <b>Methods:</b> In this study, ten hybrid compounds were synthesized by combining two known pharmaceutical scaffolds to enhance antibacterial activity and overcome resistance mechanisms. The synthesized compounds were evaluated for their antibacterial activity against five Gram-negative and seven Gram-positive bacterial strains. In silico pharmacokinetic and drug-likeness properties of selected active compounds (<b>12</b>-<b>16</b>, <b>19</b>, <b>21</b>, and <b>23</b>) were predicted using the SwissADME web tool. <b>Results:</b> Compounds <b>12-16</b>, <b>19</b>, <b>21</b>, and <b>23</b> demonstrated significant antibacterial activity, with compound <b>16</b> (a ciprofloxacin-containing hybrid) exhibiting the most potent effect, showing a minimum inhibitory concentration (MIC) of 7.8125 µg/mL against all tested bacterial strains. The in silico analysis revealed favorable pharmacokinetic profiles, drug-likeness, lipophilicity, and water solubility of most hybrid compounds. <b>Discussion:</b> The synthesized hybrid compounds exhibited enhanced antibacterial activity and desirable pharmacokinetic properties, particularly compound <b>16</b>. These findings suggest the potential of these molecules in combating bacterial pathogens, especially those implicated in co-infections in COVID-19 infections. <b>Conclusions:</b> The study presents promising hybrid antibacterial agents with potential application as adjunct therapies for treating COVID-19-associated bacterial co-infections. Further investigation is needed, which may lead to effective treatments for managing secondary bacterial infections in viral disease contexts.