Synthesis, spectral, and anti-microbial studies of thioiminium iodides and amine hydrochlorides

To avoid the undesired deprotonation during the addition of organolithium and organomagnesium reagents to ketones, the thioiminium salts, easily prepared from lactams and amides are converted into 2,2-disubstituted and 2-monosubstituted amines by reaction with simple nucleophiles such as organocerium and organocopper reagents. The reaction of thioiminium iodides with organocerium reagents derived by transmetalation of corresponding lithium reagents with anhydrous cerium(III) chloride has been investigated. These thioiminium iodides act as good electrophiles and accept alkylceriums towards bisaddition. The newly synthesized amines have been characterized by 1H and 13C NMR, IR and mass spectra. The amines have been converted into their hydrochlorides and characterized by COSY. These hydrochlorides have been subjected to antimicrobial screening with clinically isolated microorganisms, Staphylococcus aureus, Klebsiella pneumoniae, Pseudomonas aeruginosa, Salmonella typhi and Candida albicans. The hydrochlorides show quite good activity against these bacteria and fungus.

Application of an in vitro drug screening assay based on the release of phosphoglucose isomerase to determine the structure-activity relationship of thiazolides against Echinococcus multilocularis metacestodes

OBJECTIVES: The disease alveolar echinococcosis (AE), caused by the larval stage of the cestode Echinococcus multilocularis, is fatal if treatment is unsuccessful. Current treatment options are, at best, parasitostatic, and involve taking benzimidazoles (albendazole, mebendazole) for the whole of a patient's life. In conjunction with the recent development of optimized procedures for E. multilocularis metacestode cultivation, we aimed to develop a rapid and reliable drug screening test, which enables efficient screening of a large number of compounds in a relatively short time frame. METHODS: Metacestodes were treated in vitro with albendazole, the nitro-thiazole nitazoxanide and 29 nitazoxanide derivatives. The resulting leakage of phosphoglucose isomerase (PGI) activity into the medium supernatant was measured and provided an indication of compound efficacy. RESULTS: We show that upon in vitro culture of E. multilocularis metacestodes in the presence of active drugs such as albendazole, the nitro-thiazole nitazoxanide and 30 different nitazoxanide derivatives, the activity of PGI in culture supernatants increased. The increase in PGI activity correlated with the progressive degeneration and destruction of metacestode tissue in a time- and concentration-dependent manner, which allowed us to perform a structure-activity relationship analysis on the thiazolide compounds used in this study. CONCLUSIONS: The assay presented here is inexpensive, rapid, can be used in 24- and 96-well formats and will serve as an ideal tool for first-round in vitro tests on the efficacy of large numbers of antiparasitic compounds.

Membrane disrupting antimicrobial peptide dendrimers with multiple amino termini

Antimicrobial peptide dendrimer H1 Leu8(Lys-Leu)4(Lys-Phe)2Lys-LysNH2 (Lys = branching lysine) was identified by screening a 6750-membered combinatorial library by the bead-diffusion assay. Sequence variations also revealed dendrimer bH1 Leu8(Dap-Leu)4(Dap-Phe)2Dap-LysNH2 (Dap = branching 2,3-diaminopropanoic acid) as a more potent analog. H1 and bH1 showed good antimicrobial activities mediated by membrane disruption (MIC = 2–4 μg mL−1 on Bacillus subtilis and Escherichia coli) but low hemolytic activity (MHC = 310 μg mL−1 respectively >2000 μg mL−1).

Serotype distribution and antimicrobial susceptibility of group B streptococci in pregnant women: results from a Swiss tertiary centre.

OBJECTIVE To evaluate the rates of penicillin, clindamycin and erythromycin resistance and the serotype distribution among isolates of group B streptococcus (GBS) obtained from pregnant women at the University Hospital of Bern in Switzerland. METHODS We prospectively collected screening samples for GBS colonisation at the University Women's Hospital Bern, Switzerland, between March 2009 and August 2010. We included 364 GBS isolates collected from vaginal, cervical or vaginal-perianal swabs at any gestation time. The minimal inhibitory concentrations for penicillin, clindamycin and erythromycin were established using Etest with 24 hours of incubation, and inducible clindamycin resistance was tested with double disk diffusion tests. Serotyping was done with a rapid latex agglutination test or, if not conclusive, with polymerase chain-reaction (PCR) testing. We looked for significant associations between resistance patterns, age groups, serotype and ethnicity. RESULTS All isolates were susceptible to penicillin. Resistance rates were 14.5% for erythromycin and 8.2% for clindamycin. Of 364 isolates, 5.8% were susceptible to clindamycin but not to erythromycin, although demonstrating inducible clindamycin resistance. Hence, the final reported clindamycin resistance rate was 14%. Serotype III was the most frequent serotype (29%), followed by V (25%) and Ia (19%). Serotype V was associated with erythromycin resistance (p = 0.0007). In comparison with all other ethnicities, patients from Asia showed a higher proportion of erythromycin and clindamycin resistance (p = 0.018). No significant association between resistance patterns and age groups was found. CONCLUSION In pregnant women with GBS colonisation, penicillin is the antibiotic of choice for intrapartum prophylaxis to prevent neonatal early-onset GBS sepsis. In women with penicillin allergy and at high risk for anaphylactic reaction, clindamycin may be an alternative. The resistance rate for clindamycin at our institution was 14%; therefore, susceptibility must be tested before administration.