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 () and sulfonate () analogues of natural bioactive precursors were designed and synthesized. Preliminary screening against two Gram-positive ( and ) and four Gram-negative bacterial strains (, , , and ) was performed to assess the potency of these analogues as antibacterial agents. Among all triazole analogues, (derived from carvacrol) and (derived from 2-hydroxy 1,4-naphthoquinone) bearing carboxylic acid functionality emerged as potent antibacterial agents against (IC: 62.53 and 39.33 μg/mL), (IC: 36.66 and 61.09 μg/mL), and (IC: 15.28 and 22.57 μg/mL). Furthermore, and also demonstrated moderate efficacy against multidrug-resistant strains and were therefore selected for further biological studies. Compound in combination with ciprofloxacin displayed a synergistic effect on multidrug-resistant MRA11 and MRC17 strains, whereas compound was selective against MRA11 strain. Growth kinetic studies on and treated with and showed an extended lag phase. and 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 ( and ) exposed to and clearly showed morphological changes and damaged cell walls. Moreover, these compounds also significantly inhibited biofilm formation in and strains, which was visualized by scanning electron microscopic (SEM) analysis. Treatment of larvae of (an in vivo model for antimicrobial studies) with and 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.