An efficient synthetic route for preparation of antimycobacterial wollamides and evaluation of their in vitro and in vivo efficacy.

A convenient solid phase peptide synthetic (SPPS) route is reported for the preparation of antimycobacterial wollamides. The method is based on on-resin head-to-tail cyclization and is fast, efficient and amenable to automation. The in vitro antimycobacterial activities of the newly synthesized wollamides were evaluated against M. tuberculosis H37Rv (Mtb H37Rv). To assess their drug-likeness, in vitro pharmacokinetic (ADME) profiling was also performed. For wollamides with potent extracellular potency, intracellular activities and in vivo efficacy were determined. The results disclose the potent antimycobacterial (MICMtb H37Rv = 1.1 µM) and suitable drug-like properties of wollamide A (4b). Out of the synthesized wollamides, four compounds (4b-e) exhibited potent intracellular activities against Mtb H37Rv infected human macrophages (IC50 = 0.2-1.3 µM). Results of in vivo blood exposure and efficacy assays for 4d and 4e are discussed.

Synthesis and biological evaluation of some pyrazole derivatives as anti-malarial agents.

Novel series of pyrazole derivatives were synthesized and tested for their in vivo anti-malarial activity using mice infected with chloroquine sensitive P. berghei at a dose level of 50 µmol/kg. The most active compounds were further tested in vitro against chloroquine resistant (RKL9) strain of P. falciparum. The in vivo anti-malarial activity study indicated that compounds 2a, 2b, 8a and 8b had mean percent suppression of 85%, 83%, 95% and 97%, respectively at equimolar dose level of the standard drug chloroquine diphosphate. Moreover, compounds 2a, 2b, 8a and 8b showed in vitro IC(50) values lower (p < 0.05) than that of the standard drug chloroquine phosphate (0.188 ± 0.003 µM) using the RKL9 strain. Compound 8b was the most active with IC(50) of 0.033 ± 0.014 µM. Generally, among the tested compounds, those containing a free carboxylic acid functional group on the pyrazole ring were the most active and this finding was supported by the docking results performed for the active compounds. The acute toxicity studies of the active compounds revealed that they have a good safety profile.

Design, synthesis and structure-activity relationship study of wollamide B; a new potential anti TB agent.

Wollamide B is a cationic antimycobacterial cyclohexapeptide that exhibits activity against Mycobacterium bovis (M. bovis) (IC50 of 3.1 µM). Aiming to define its structural activity relationship (SAR), optimizing potency and pharmacokinetic properties, libraries of analogues were synthesized following a standard Fmoc-based solid phase peptide synthesis approach. The antimycobacterial activities of wollamide B and all the synthesized analogues were tested against Mycobacterium tuberculosis (Mtb) H37Rv. Parallely, in vitro drug metabolism and pharmacokinetic (ADME) profiling was done for the synthesized compounds to evaluate their drug likeness. Among the 25 synthesized wollamides five of them showed potent activities with MICs ≤ 3.1 µM and found to be nontoxic against human HepG2 cells up to 100 µM. The results of the in vitro ADME profiling revealed the remarkable plasma stability and very good aqueous solubility of the class in general while the metabolic stability was found to be moderate to low. Of particular note, compounds 7c (MIC = 1.1 µM) and 13c (0.6 µM) that exhibited good balance of antimycobacterial activity vs. optimal pharmacokinetic properties could be used as a new lead for further development.

Microbiological Safety of Street Vended Foods in Jigjiga City, Eastern Ethiopia.

BACKGROUND: Food safety problems are particularly becoming an increasingly serious threat to public health in developing countries. This study was conducted to assess microbiological safety of street vended foods from May to November, 2014 in Jigjiga City. METHODS: A cross-sectional design was used to answer questions concerning the current status of food hygiene and sanitation practire of street food vending sites. Interview and observational assessments were used to collect socio-demographic data about street food venders. One hundred thirty-two samples of street foods were aseptically collected from four 'kebeles' of Jigjiga City. Both descriptive and analytical statistical methods were applied. RESULTS: The majority of the street food vendors were women, 120(90.9%), with the average age group of 23-49 years, (42.85%), and 99(66.7%) them were illiterate. The study revealed that 95(72%) of the food samples had pathogenic bacterial contaminations. Three different bacterial species were isolated: E. coli 68(51.5%), S. aureus 85(64.4%) and 26(19.7%) Salmonella species. The highest incidence of S. aureus 23/33(69%) was seen in 'Sambusa'; the highest incidence of E. coli 24/33(73.5%) was observed in 'Pasta', while the highest Salmonella incidence was observed in 'Ades'. CONCLUSION: This study revealed that there is a reasonable gap on food safety knowledge among street food venders. The microbial profile was also higher compared to standards set by the World Health Organization. Due attention should be given by the government to improve knowledge about food safety and the quality standard of street foods sold in the City.