Abstract
Pleuromutilin is a fungal diterpene natural product with antimicrobial properties, semisynthetic derivatives of which are used in veterinary and human medicine. The development of bacterial resistance to pleuromutilins is known to be very slow, which makes the tricyclic diterpene skeleton of pleuromutilin a very attractive starting structure for the development of new antibiotic derivatives that are unlikely to induce resistance. Here, we report the very first synthetic modifications of pleuromutilin and lefamulin at alkene position C19–C20, by two different photoinduced addition reactions, the radical thiol-ene coupling reaction, and the atom transfer radical additions (ATRAs) of perfluoroalkyl iodides. Pleuromutilin were modified with the addition of several alkyl- and aryl-thiols, thiol-containing amino acids and nucleoside and carbohydrate thiols, as well as perfluoroalkylated side chains. The antibacterial properties of the novel semisynthetic pleuromutilin derivatives were investigated on a panel of bacterial strains, including susceptible and multiresistant pathogens and normal flora members. We have identified some novel semisynthetic pleuromutilin and lefamulin derivatives with promising antimicrobial properties.
Highlights
Several novel semisynthetic pleuromutilin-moieties are Several novel semisynthetic pleuromutilin-moieties are known known from from the the literature, literature, mainly obtained by modifications at the glycolic ester residue. These modifications have shifted the antibacterial effect of these drugs to a broader spectrum, modifications have shifted the antibacterial effect of these drugs to a broader spectrum, and and the the activities activities against against Gram-negative
Novel novel pleuromutilin derivatives with substituted thiadiazole and triazole moieties pleuromutilin derivatives with substituted thiadiazole [16] and triazole moieties [17] at at position C-22 have been published as promising antibacterial agents
Gram-negative pathogens, the same modification of the parent pleuromutilin (8) led to a slight decrease in the antibacterial effect [18]
Summary
The WHO have stated that “antibiotic resistance is putting the achievements of modern medicine at risk” [1]. This statement summarizes the difficulty of antibiotic developments in one sentence. Modern medicinal chemistry sometimes finds “forgotten” drugs for improvement; previously discovered drugs can find new thera-. Modern medicinal chemistry sometimes finds “forgotten” drugs for improvement; previously discovered drugs can find new therapeutic applications. Some synthetic modifications can enhance the antibacterial effect and/or break down antibiotic resistance. Gram-positive bacteria by acting as a peptidyl inhibitor topilus fungi, a against secondary metabolite diterpene with a tricyclic skeleton.tranferase. Semisynthetic derivatives [3–10], bearing basicdeveloped substituentfor at human the C14 and glycolic ester moiety the parentand pleuromutilin, havelong been developed human and veterinary erinary use.
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