Synthesis and antimicrobial activities of hexahydroimidazo[1,5- a]pyridinium bromides with varying benzyl substituents

• Published in: European journal of medicinal chemistry 2011-07, Vol.46 (7), p.2895-2900
• Main Authors: Türkmen, Hayati, Ceyhan, Nur, Ülkü Karabay Yavaşoğlu, N., Özdemir, Güven, Çetinkaya, Bekir
• Format: Article
• Language: English
• Subjects: Acute toxicity; Anti-Bacterial Agents - chemical synthesis; Anti-Bacterial Agents - pharmacology; Antibacterial agents; Antibiotics. Antiinfectious agents. Antiparasitic agents; Antifungal agents; Antifungal Agents - chemical synthesis; Antifungal Agents - pharmacology; Antimicrobial activities; Biological and medical sciences; Bromides - chemistry; Candida - drug effects; Candida - growth & development; Enterobacteriaceae - drug effects; Enterobacteriaceae - growth & development; General aspects; Hexahydroimidazo[1,5- a]pyridinium bromides; Imidazoles - chemistry; Imidazolinium salts; Medical sciences; Microbial Sensitivity Tests; Micrococcus luteus - drug effects; Micrococcus luteus - growth & development; Pharmacology. Drug treatments; Pyridinium Compounds - chemical synthesis; Pyridinium Compounds - pharmacology; Staphylococcus - drug effects; Staphylococcus - growth & development; Structure-Activity Relationship
• ISSN: 0223-5234; 1768-3254
• DOI: 10.1016/j.ejmech.2011.04.012

Variously substituted benzyl bromides were employed to quaternize hexahydrobenzylimidazo[1,5- a]pyridine ( A) and the resulting bromides ( 1– 11) were evaluated for their in vitro antimicrobial activity against 10 pathogenic microorganisms: Staphylococcus aureus, Staphylococcus epidermidis, Bacillus cereus, Micrococcus luteus, Proteus vulgaris, Escherichia coli, Salmonella typhimurium, Klebsiella pneumonia, Candida albicans and Candida krusei. Antimicrobial activities were surprisingly high (MIC: 0.78–400 μg/mL) and the sensitivity of the salts tested has been found to depend strongly both on the benzyl substituents and the microorganisms used. However, the correlation observed between antimicrobial activity and calculated partition coefficient (Clog P) was poor. Acute toxicity assessment of these salts showed LD 50 of 757–2000 mg/kg, after oral administration in mice in 24 h. Most of the title bromides ( 1– 11) showed moderate to very good antibacterial and antifungal activities (MIC: 0.78–400 μg/mL), when compared to the standard drugs. Their acute toxicity in mice ranges from 757 to 2000 mg/kg. [Display omitted] ► The salts, derived from quaternization of hexahydroimidazo[1,5- a]pyridine with substituted benzyl bromides, were fully characterized and screened for in vitro antimicrobial activity. ► The N 1–C 5 positions of the imidazolinium ring in compounds are of major importance for the antimicrobial activity. ► The electron-withdrawing substituents (Cl, CN, CF 3) at the p-position of the phenyl ring increases antibacterial and antifungal activities when compared to the other substituents (H, CH 3, tBu).