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

Abstract

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 (5a–x) and sulfonate (7a–j) analogues of natural bioactive precursors were designed and synthesized. Preliminary screening against two Gram-positive (Streptococcus pneumoniae and Enterococcus faecalis) and four Gram-negative bacterial strains (Pseudomonas aeruginosa, Salmonella enterica, Klebsiella pneumoniae, and Escherichia coli) was performed to assess the potency of these analogues as antibacterial agents. Among all triazole analogues, 5e (derived from carvacrol) and 5u (derived from 2-hydroxy 1,4-naphthoquinone) bearing carboxylic acid functionality emerged as potent antibacterial agents against S. pneumoniae (IC50: 62.53 and 39.33 μg/mL), E. faecalis (IC50: 36.66 and 61.09 μg/mL), and E. coli (IC50: 15.28 and 22.57 μg/mL). Furthermore, 5e and 5u also demonstrated moderate efficacy against multidrug-resistant E. coli strains and were therefore selected for further biological studies. Compound 5e in combination with ciprofloxacin displayed a synergistic effect on multidrug-resistant E. coli MRA11 and MRC17 strains, whereas compound 5u was selective against E. coli MRA11 strain. Growth kinetic studies on S. pneumoniae and E. coli treated with 5e and 5u showed an extended lag phase. 5e and 5u 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 (S. pneumoniae and E. coli) exposed to 5e and 5u clearly showed morphological changes and damaged cell walls. Moreover, these compounds also significantly inhibited biofilm formation in S. pneumoniae and E. coli strains, which was visualized by scanning electron microscopic (SEM) analysis. Treatment of larvae of Galleria mellonella (an in vivo model for antimicrobial studies) with 5e and 5u 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.

Galleria mellonella as a consolidated in vivo model hosts: New developments in antibacterial strategies and novel drug testing

“…Results showed nontoxic behaviour towards the larvae viability. Moreover, the hemocyte density of larvae treated with tested compounds was not significantly affected if compared to untreated ones [95].…”

“…The in vivo toxicity assay using G. mellonella was performed on two triazole analogues (one derived from carvacrol and the other derived from 2-hydroxy 1,4-naphthoquinone) bearing carboxylic acid, which had previously been tested for their antibacterial activity in vitro [95]. Results showed nontoxic behaviour towards the larvae viability.…”

1,2,3-Triazole–quinazolin-4(3H)-one conjugates: evolution of ergosterol inhibitor as anticandidal agent

“…31.25 mg mL À1 for C. albicans. At predetermined time periods (0, 2,4,6,8,10,12,14,16,18,20,22, and 24 h) aer incubation with agitation at 37 C, 1 mL aliquot to each sample was removed from the conical ask and growth was measured turbidometrically at 600 nm using Thermo Multiskan spectrophotometer. Optical density (O.D.)…”

“…In our continuous efforts to design biologically active heterocycles, [12][13][14][15][16][17] we hypothesized albaconazole as a model for preparation of 1,2,3-triazole derivatives of quinazolin-4(3H)-one (5a-q and 6a-q) and studied their antifungal properties. Further, single crystal X-ray study of compounds 2 and 5c has been reported.…”

Catalyst- and solvent-free synthesis of 2-fluoro-N-(3-methylsulfanyl-1H-1,2,4-triazol-5-yl)benzamide through a microwave-assisted Fries rearrangement: X-ray structural and theoretical studies

“…Among the broad range of privileged structures, triazole represents one of the most prominent classes of N-heterocyclic scaffolds for novel synthetic drug discovery due to its broad range of pharmacological and biological activities (Jagdish et al, 2013;Kantheti et al, 2015;Nocentini et al, 2016;Aneja et al, 2018). Thought the triazole moiety has not been found in natural products, the development of efficient and straightforward methods for the preparation of triazole derivatives has greatly increased over the last two decades.…”