Natural Product-Based 1,2,3-Triazole/Sulfonate Analogues as Potential Chemotherapeutic Agents for Bacterial Infections

Despite the vast availability of antibiotics, bacterial infections remain a leading cause of death worldwide. In an effort to enhance the armamentarium against resistant bacterial strains, 1,2,3-triazole (<b>5a-x</b>) and sulfonate (<b>7a-j</b>) analogues of natural bioactive precursors were designed and synthesized. Preliminary screening against two Gram-positive (<i>Streptococcus pneumoniae</i> and <i>Enterococcus faecalis</i>) and four Gram-negative bacterial strains (<i>Pseudomonas aeruginosa</i>, <i>Salmonella enterica</i>, <i>Klebsiella pneumoniae</i>, and <i>Escherichia coli</i>) was performed to assess the potency of these analogues as antibacterial agents. Among all triazole analogues, <b>5e</b> (derived from carvacrol) and <b>5u</b> (derived from 2-hydroxy 1,4-naphthoquinone) bearing carboxylic acid functionality emerged as potent antibacterial agents against <i>S. pneumoniae</i> (IC₅₀: 62.53 and 39.33 μg/mL), <i>E. faecalis</i> (IC₅₀: 36.66 and 61.09 μg/mL), and <i>E. coli</i> (IC₅₀: 15.28 and 22.57 μg/mL). Furthermore, <b>5e</b> and <b>5u</b> also demonstrated moderate efficacy against multidrug-resistant <i>E. coli</i> strains and were therefore selected for further biological studies. Compound <b>5e</b> in combination with ciprofloxacin displayed a synergistic effect on multidrug-resistant <i>E. coli</i> MRA11 and MRC17 strains, whereas compound <b>5u</b> was selective against <i>E. coli</i> MRA11 strain. Growth kinetic studies on <i>S. pneumoniae</i> and <i>E. coli</i> treated with <b>5e</b> and <b>5u</b> showed an extended lag phase. <b>5e</b> and <b>5u</b> did not show significant cytotoxicity up to 100 μg/mL concentration on human embryonic kidney (HEK293) cells. Transmission electron microscopic (TEM) analysis of bacterial cells (<i>S. pneumoniae</i> and <i>E. coli</i>) exposed to <b>5e</b> and <b>5u</b> clearly showed morphological changes and damaged cell walls. Moreover, these compounds also significantly inhibited biofilm formation in <i>S. pneumoniae</i> and <i>E. coli</i> strains, which was visualized by scanning electron microscopic (SEM) analysis. Treatment of larvae of <i>Galleria mellonella</i> (an in vivo model for antimicrobial studies) with <b>5e</b> and <b>5u</b> did not cause an alteration in the hemocyte density, thereby indicating lack of an immune response, and were nontoxic up to a concentration of 2.5 mg/mL.