Abstract:: Motivated by evidence garnered from literature probing the use of triazoles in drug discovery and development we reported the utilization of bioisosteric replacement and molecular hybridization in this review. Bio-isosteric replacement has played a significant role in modulating rapid and versatile strategy in synthesizing molecules with multifaceted medicinal properties. Molecular hybridization seeks to conjugate two molecular fragments with diverse applications under very mild reaction conditions. In this regard, 1, 2, 3-triazole is a well-known scaffold with widespread occurrence in medicinal compounds. It is characterized to have several bioactivities such as anti-microbial, anti-cancer, anti-viral, analgesic, anti-inflammatory effects. Furthermore, the structural features of 1,2,3-triazoles enable it to mimic different functional groups justifying its use as bio-isostere for the synthesis of new molecules of medicinal interest which we have reported briefly.
Acetaminophen (AP) is a popularly recommended over-the-counter analgesic–antipyretic in clinical use. However, the drug is handicapped by the occurrence of hepatotoxic insult following acute ingestion. Consequently, AP-induced hepatotoxicity is often implicated in accidental or suicidal overdose. In the current study, we investigated the potential of bioisosteric replacement of amide in AP with 1,2,3-triazoles in curbing AP-induced hepatotoxicity. The therapeutic utility of synthesized bioisosteres was established by careful tailoring and optimization of the synthetic methodology along with detailed toxicological testing of pharmacologically potent acetaminophen–triazole derivatives (APTDs). Along the same lines, we herein report a series of 17 novel APTDs synthesized via aromatic substitution using sodium azide, l-proline, and copper iodide followed by click reaction with substituted alkynes using copper sulfate and sodium ascorbate. Pharmacological evaluation of synthesized APTDs revealed that, out of the series of 17 compounds, 5a and 5e were found to be most efficacious in exerting anti-inflammatory, analgesic, and antipyretic activity in an animal model. Further toxicity studies documented that, in both acute and sub-acute toxicology, AP administration caused significant hepatotoxicity, which was found to be a consequence of ROS-mediated oxidative stress. Potent APTDs (5a and 5e), on the other hand, revealed no adverse event in both acute and sub-toxicological analyses. Median lethal dose (LD50) and no observed adverse effect level (NOAEL) values for 5a and 5e were found to be >1000 mg/kg and 2000 mg/kg, respectively. The human equivalent dose, defining the maximum safe concentration of a compound in a human’s physiology, was found to be 27.68 mg/kg for the most potent APTDs (5a and 5e). Thus, it can be concluded that triazole incorporation into AP nucleus produced conjugates devoid of hepatotoxic manifestations, having the added advantage of anti-inflammatory efficacy along with analgesic and antipyretic potency.
A series of hybrid antimicrobial compounds were prepared by carboxylic acid protection of 6-aminopenicillanic acid using benzyl alcohol and thionyl chloride succeeded by azide displacement using trifluoromethanesulfonyl azide in dichloromethane. The azide thus formed was reacted with substituted alkynes to furnish benzyl-protected penicillin–triazole conjugates. Benzyl deprotection of the conjugates resulted in furnishing PNTCs under water methanol mixture using Pd/C as a catalyst. The PNTCs (7a–j) formed were screened for in vitro antibacterial potency against pathogenic strains of Escherichia coli, Pseudomonas aeruginosa, Staphylococcus aureus, and Streptococcus pyogenes and antifungal potency against Candida albicans, Aspergillus niger, and Aspergillus clavatus. Further antimicrobial evaluation revealed compounds 7c, 7d, 7e, 7g, and 7i to be the most compounds of the series with minimum inhibitory concentration value for antibacterial in the range 0.5–50 μg/mL and for antifungal in the range 9–300 μg/mL. Toxicological analysis documented for compounds 7c, 7d, 7e, 7g, and 7i revealed compound 7i to be the most promising member of the series with 1000 and 500 mg/kg LD50, and no-observed-adverse-effect level to facilitate future clinical studies of the same.
Background: Reduced efficacy of the available antifungal drugs is the major public health concern of the population all over the world. Despite significant advances in the treatment of these life-threatening infections, severe toxicity and increasing median effective dose have limited the efficacy of frontline therapy applicable against them. Objective: The quintessential occurrence of systemic toxicity handicaps the clinical utility of currently available antifungal drugs. 1,2,3-Triazoles in the same context are relatively less toxic. Consequently, conjugation of quinine with the triazole moiety for enhanced efficacy and reduced toxicity have been excessively envisaged and reported in the context of a range of activities ranging from inflammation to cancer, however lack of toxicity profile sabotages the translation of the laboratory prototype into successful clinical practice. Method: We herein report the synthesis and characterization of a series of quinine triazole hybrids via o-mesylation followed by azide displacement, then reacting it with aliphatic and aromatic alkynes in water: t-butanol mixture. The reaction was carried in the presence of copper sulphate and sodium ascorbate. Product 6a-s was screened for in-vitro antifungal activity. The in-vitro antifungal potential of synthesized compounds was estimated against prominent fungal strains (Candida albicans, Aspergillus niger and, Aspergillus clavatus). Results: The results showed that some of the synthesized compounds exhibited marked activity. Compounds 6a, 6b, 6c, 6d, 6g, and 6q showed significant antifungal activity at micromolar concentration. The studies revealed that some of the compounds exhibited activities more than that of reference drugs. The compound containing thiazole ring 6c is the most potent compound of the series. Conclusion: Compound 6c was found to be the most vigorous against C. albicans, A. niger, A. clavatus with MIC values of 19.4, 12.7, and 21.3 μM/mL, respectively. Our SAR study revealed that the introduction of the 1,2,3-triazole ring in the structure of quinine modulated its potency for treating fungal infection.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.