Synthesis, Pharmacological and Toxicological Screening of Penicillin-Triazole Conjugates (PNTCs)

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.