Design and synthesis of novel 2H-chromen-2-one derivatives bearing 1,2,3-triazole moiety as lead antimicrobials

• Published in: Bioorganic & medicinal chemistry letters 2014-04, Vol.24 (7), p.1795-1801
• Main Authors: Kushwaha, Khushbu, Kaushik, Nagendra, Lata, Jain, Subhash C.
• Format: Article
• Language: English
• Subjects: 1,2,3-Triazole; 2H-Chromen-2-one; Animals; Anti-Bacterial Agents - administration & dosage; Anti-Bacterial Agents - chemistry; Anti-Bacterial Agents - pharmacology; Antibacterial activity; Antifungal activity; Antifungal Agents - administration & dosage; Antifungal Agents - chemistry; Antifungal Agents - pharmacology; Aspergillus flavus; Aspergillus fumigatus; Aspergillus niger; Bacillus subtilis; Bacteria - drug effects; Candida albicans; Click reaction; Coumarins - administration & dosage; Coumarins - chemistry; Coumarins - pharmacology; Cup-plate method; Daphnia; Dose-Response Relationship, Drug; Drug Design; Escherichia coli; Fungi - drug effects; Klebsiella pneumoniae; Mice; Microbial Sensitivity Tests; Molecular Structure; Propargyl amines; Pseudomonas aeruginosa; Rats; Salmonella typhi; Staphylococcus aureus; Staphylococcus epidermis; Structure-Activity Relationship; Triazoles - administration & dosage; Triazoles - chemistry; Triazoles - pharmacology
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2014.02.027

A series of novel 1,2,3-triazolylcoumarins were designed, synthesized and evaluated for their in vitro antimicrobial activity. A series of novel 2H-chromen-2-one derivatives decorated with 1,2,3-triazole moiety were designed and synthesized using the click reaction of azidoalkyloxy-2H-chromen-2-ones with different propargylamines. Propargylamines were obtained by alkylation of various heterocyclic amines with propargyl bromide. Newly synthesized compounds and intermediates were evaluated for their antifungal activity against four fungi (Aspergillus niger, Aspergillus fumigatus, Aspergillus flavus and Candida albicans). Antibacterial studies were also carried out against three Gram-positive bacteria (Staphylococcus aureus, Bacillus subtilis and Staphylococcus epidermis) and four Gram-negative bacteria (Escherichia coli, Pseudomonas aeruginosa, Salmonella typhi and Klebsiella pneumoniae). In vitro, bioassay results showed that all the synthesized compounds exhibited excellent activity against fungal strains Aspergillus fumigatus, Aspergillus flavus and Candida albicans. Interestingly, all the compounds have shown even superior activity than the reference drug miconazole against Aspergillus fumigatus. Morpholine and N-acetyl piperazine containing compounds 10c and 10e have shown promising activity against various bacterial strains. Compound 10e was found to be most active against Pseudomonas aeruginosa. Based on, in silico pharmacokinetic studies, compounds 10a–e were identified as lead compounds for future investigation due to their lower toxicity, high drug score values and good oral bioavailability as per OECD guidelines.