Diastereoselective Synthesis of Potent Antimalarial Cis-ß-lactam Agents.

Fifteen novel ß-lactams bearing N-ethyl tert-butyl carbamate group 5a-o and fifteen N-(2- aminoethyl) ß-lactams 6a-o were synthesized by [2+2] ketene-imine cycloaddition reaction (Staudinger). The cycloaddition reaction was found to be totally diastereoselective leading exclusively to theformation of cis-ß-lactam derivatives. These newly synthesized ß-lactams were evaluated for their antimalarial activity against p. falciparum K14 resistant strain and showed good to excellent EC50 values. Of the thirty ß-lactams tested, 5 h, 6a and 6c showed IC50 < 20 µM while 5b, 5c, 5e, 5f, 5g, 5i, 5j, 6d, 6g and 6h exhibited IC50 <50 . Compounds 5c, 5h, and 5q-t were examined for their anticancer properties against K562 Leukemia cell line and 5s showed the best activity. Compounds 3a-j, 5a-o, 6a-o, were tested against S. aureus , E. coli, C. albicans and showed no activity below 125 µg/mL.

Synthesis of New ß-Lactams Bearing the Biologically Important Morpholine Ring and POM Analyses of Their Antimicrobial and Antimalarial Activities.

Some new ß-lactams bearing biologically important morpholine ring have been synthesized by acylation of amino ß-lactams in the presence of morpholine-4-carbonyl chloride. These novel ß-lactams were prepared under mild reaction conditions without any solvent in short reaction times. Their biological activities have been examined against microbial agents such as Staphylococcus aureus (S. aureus), Escherichia coli (E. coli), Pseudomonas aeruginosa (P. aeruginosa) and fungi such as Candida albicans (C. albicans) and Candida glabrata (C. glabrata). They have been also tested against Plasmodium falciparum K14 resistant strain and showed moderate to good IC50 values.

Soluble squalamine tablets for the rapid disinfection of home nebulizers of cystic fibrosis patients.

BACKGROUND: The bacterial contamination of nebulizers represents a major problem for cystic fibrosis (CF) patients that can lead to reduced nebulizer performance and increase the risk of patient reinfection by the contaminating bacteria. OBJECTIVE: We investigated the potential use of squalamine, a broad-spectrum antimicrobial compound, as a nebulizer disinfectant. METHODS: Pari LC nebulizers were artificially contaminated with a suspension of bacteria (Staphylococcus aureus and Pseudomonas aeruginosa; 10(8) CFU/mL) and fungi (Candidida albicans and Aspergilus niger; 10(7) CFU/mL) and then disinfected by immersion in squalamine solution for 20 min. Glutaraldehyde and Korsolex peracetic acid were used as disinfectant controls. RESULT: We found that 0.5 g/L squalamine reduced the levels of viable S. aureus and P. aeruginosa by 5 log(10) and the level of viable C. albicans by 4 log(10) after 20 min. A concentration of 2 g/L was needed to reduce the level of A. niger cells by 4 log(10) in 6 hours. Finally, a formulation of squalamine in the form of a soluble disinfecting tablet containing 2.5% (w/w) squalamine was developed and successfully applied for nebulizer disinfection. CONCLUSION: Our results suggest that aminosterol derivatives may be used by CF patients for rapid and easy home nebulizer disinfection and that soluble tablets may be developed for this purpose.

Synthesis of new 3,20-bispolyaminosteroid squalamine analogues and evaluation of their antimicrobial activities.

3,20-Amino- and polyaminosteroid analogues of squalamine and trodusquemine were synthesized involving a stereoselective titanium reductive amination reaction in high chemical yields in numerous cases. These derivatives were evaluated for their in vitro antimicrobial properties against references and clinical bacterial strains exhibiting minimum inhibitory concentrations of 2.5-40 µg/mL. The mechanism of action of these derivatives was determined using bioluminescence for ATP efflux measurements and fluorescence methods for membrane depolarization assays.

Squalamine ointment for Staphylococcus aureus skin decolonization in a mouse model.

OBJECTIVES: Staphylococcus aureus colonization of the skin and the nostrils remains a major cause of surgical-site infections despite preoperative and preventive procedures. To date, many compounds have been used for S. aureus decolonization, including mupirocin ointments and antiseptics, with variable results. The emergence of mupirocin-resistant S. aureus strains has led to the search for new antimicrobial agents specifically for S. aureus decolonization. In this work we evaluated squalamine and related parent-derived ointments (1%) as potential new compounds for S. aureus decolonization in a new mouse model. METHODS: We report the development and application of squalamine and related parent-derived ointments in a new mouse skin model. After skin shaving, mice were colonized with an S. aureus suspension that was calibrated to 104-106 cfu/mL. The remaining bacterial load was monitored for 2 days after a single application of squalamine by spreading. RESULTS: We found that S. aureus colonization of the skin was stable for at least 2 days before it was naturally eliminated. Using this model we found that squalamine ointment (1%) could reduce S. aureus viable cells by up to 4 log with a single, 1 h application of ointment, whereas mupirocin application reduced viable cell numbers by only 1.3 log during that same time (P < 0.05). CONCLUSIONS: Our results suggest that such compounds may be useful for S. aureus nasal and skin decolonization and may constitute a potent alternative for skin and nasal antisepsis before surgery.