RESUMEN
Total synthesis of bottromycin A2 can be accomplished through a diastereoselective Mannich reaction of a chiral sulfinamide, mercury-mediated intermolecular amidination, and cyclization of a constrained tetracyclic peptide. Exploitation of this process allowed the synthesis of several novel bottromycin analogs. The antimicrobial activity of these analogs was evaluated in vitro against Gram-positive bacteria, such as methicillin resistant Staphylococcus aureus (MRSA) and vancomycin resistant enterococci (VRE). Structure-activity relationships were explored taking into consideration the unique three-dimensional structure of the compounds. Notably, one of the new analogs devoid of a methyl ester, which is known to lower the in vivo efficacy of bottromycin, exhibited antibacterial bioactivity comparable to that of vancomycin.
Asunto(s)
Antibacterianos/síntesis química , Antibacterianos/farmacología , Staphylococcus aureus Resistente a Meticilina/efectos de los fármacos , Pruebas de Sensibilidad Microbiana , Péptidos Cíclicos/síntesis química , Péptidos Cíclicos/farmacología , Resistencia a la Vancomicina/efectos de los fármacosRESUMEN
The impact of ivermectin on adult snails of the genus Biomphalaria (B. glabrata, B. tenagophila and B. straminea), B. glabrata infected with Schistosoma mansoni, snail egg-masses cercariae and miracidia, as well as on guppy fish (Poecilia reticulata) was examined and evaluated. Biomphalaria snails, egg-masses, parasite stages and guppies were all exposed to different concentrations of ivermectin for 24 h, followed by regular observations of mortality. The calculated lethal doses of ivermectin were around an LD50 of 0.03 µg ml-1, and an LD90 of 0.3 µg ml-1 for the three species of snails. Specimens of B. glabrata actually shedding parasite cercariae all died when exposed to ivermectin at a concentration of a mere 0.01 µg ml-1. Ivermectin B1a, the major (80%) component of commercially available ivermectin, proved to be inactive, and it was the minor (20%) component, ivermectin B1b, which caused snail death. Snail egg-masses were not affected, even at the highest concentration of 100 µg ml-1. With respect to S. mansoni parasite stages, 0.2 µg ml-1 ivermectin killed 50% of cercariae and miracidia within five minutes, rising to 90% after 30 min. Mortality of guppy fish within 24 h of exposure to ivermectin at concentrations of 0.5 µg ml-1 and 0.01 µg ml-1, were 100% and 30%, respectively. The concentration of 0.01 µg ml-1 that killed Schistosoma mansoni-infected snails only caused 30% mortality in guppy fish. Ivermectin can be considered a promising molluscicide, especially as it is more potent against infected snails than uninfected ones, although it has no impact on egg-masses. Ivermectin and its derivatives could be explored in the search for a new agent to help control schistosomiasis transmission.