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Total Synthesis of (+)-Pleuromutilin.

ABSTRACT: An 18-step synthesis of the antibiotic (+)-pleuromutilin is disclosed. The key steps of the synthesis include a highly stereoselective SmI2-mediated cyclization to establish the eight-membered ring and a stereospecific transannular [1,5]-hydrogen atom transfer to set the C10 stereocenter. This strategy was also used to prepare (+)-12-epi-pleuromutilin. The chemistry described here will enable efforts to prepare new mutilin antibiotics.

SUBMITTER: Farney EP

PROVIDER: S-EPMC5988231 | biostudies-literature | 2018 Jan

REPOSITORIES: biostudies-literature

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Total Synthesis of (+)-Pleuromutilin.

Farney Elliot P EP Feng Sean S SS Schäfers Felix F Reisman Sarah E SE

Journal of the American Chemical Society 20180117 4

An 18-step synthesis of the antibiotic (+)-pleuromutilin is disclosed. The key steps of the synthesis include a highly stereoselective SmI<sub>2</sub>-mediated cyclization to establish the eight-membered ring and a stereospecific transannular [1,5]-hydrogen atom transfer to set the C10 stereocenter. This strategy was also used to prepare (+)-12-epi-pleuromutilin. The chemistry described here will enable efforts to prepare new mutilin antibiotics. ...[more]

PMID: 29323492

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A modular and enantioselective synthesis of the pleuromutilin antibiotics.

Project description:The tricyclic diterpene fungal metabolite (+)-pleuromutilin has served as a starting point for antibiotic development. Semisynthetic modification of its glycolic acid subunit at C14 provided the first analogs fit for human use, and derivatization at C12 led to 12-epi-pleuromutilins with extended-spectrum antibacterial activity, including activity against Gram-negative pathogens. Given the inherent limitations of semisynthesis, however, accessing derivatives of (+)-pleuromutilin with full control over their structure presents an opportunity to develop derivatives with improved antibacterial activities. Here we disclose a modular synthesis of pleuromutilins by the convergent union of an enimide with a bifunctional iodoether. We illustrate our approach through synthesis of (+)-12-epi-mutilin, (+)-11,12-di-epi-mutilin, (+)-12-epi-pleuromutilin, (+)-11,12-di-epi-pleuromutilin, and (+)-pleuromutilin itself in 17 to 20 steps.

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A concise synthesis of the molecular framework of pleuromutilin.

Project description:Two syntheses of the tricyclic carbon skeleton of pleuromutilin are reported. Diastereoselective 1,4-conjugate additions were used to elaborate bicyclic precursors at an early stage of each route, while ring-forming olefin metatheses were executed to complete the pleuromutilin carbon framework. The congeners prepared are appropriately functionalized to enable access to diverse pleuromutilin analogues.

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Synthesis and Biological Activity Evaluation of Novel Heterocyclic Pleuromutilin Derivatives.

Project description:A series of pleuromutilin derivatives were synthesized by two synthetic procedures under mild reaction conditions and characterized by Nuclear Magnetic Resonance (NMR), Infrared Spectroscopy (IR), and High Resolution Mass Spectrometer (HRMS). Most of the derivatives with heterocyclic groups at the C-14 side of pleuromutilin exhibited excellent in vitro antibacterial activities against Staphylococcus aureus, methicillin-resistant Staphylococcus aureus (MRSA), methicillin-resistant Staphylococcus epidermidis (MRSE), and vancomycin-resistant Enterococcus (VRE) in vitro antibacterial activity. The synthesized derivatives which contained pyrimidine rings, 3a, 3b, and 3f, displayed modest antibacterial activities. Compound 3a, the most active antibacterial agent, displayed rapid bactericidal activity and affected bacterial growth in the same manner as that of tiamulin fumarate. Moreover, molecular docking studies of 3a and lefamulin provided similar information about the interactions between the compounds and 50S ribosomal subunit. The results of the study show that pyrimidine rings should be considered in the drug design of pleuromutilin derivatives.

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Expanding the pleuromutilin class of antibiotics by de novo chemical synthesis.

Project description:New pleuromutilin-like compounds were synthesized in approximately 11 steps from 3-allylcyclopent-2-enone by a strategy featuring sequential carbonyl addition reactions. Several analogs possessing the C14 tiamulin ester side chain displayed activity in a Mycobacterium tuberculosis mc(2)7000 assay. The results described herein provide a basis for further efforts to expand the structural and stereochemical diversity of the pleuromutilin class of bacterial protein synthesis inhibitors through advances in chemical synthesis.

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Synthesis and biological evaluation of new pleuromutilin derivatives as antibacterial agents.

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Synthesis and Pharmacological Evaluation of Novel Pleuromutilin Derivatives with Substituted Benzimidazole Moieties.

Project description:A series of novel pleuromutilin derivatives with substituted benzimidazole moieties were designed and synthesized from pleuromutilin and 5-amino-2-mercaptobenzimidazole through sequential reactions. All the newly synthesized compounds were characterized by IR, NMR, and HRMS. Each of the derivatives was evaluated in vitro for their antibacterial activity against Escherichia coli (E. coli) and five Gram (+) inoculums. 14-O-((5-amino-benzimidazole-2-yl) thioacetyl) mutilin (3) was the most active compound and showed highest antibacterial activities. Furthermore, we evaluated the inhibition activities of compound 3 on short-term S. aureus and MRSA growth and cytochrome P450 (CYP). The bioassay results indicate that compound 3 could be considered potential antibacterial agents but with intermediate inhibition of CYP3A4.

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Chemical synthesis and biological activities of novel pleuromutilin derivatives with substituted amino moiety.

Project description:Novel pleuromutilin derivatives designed based on the structure of valnemulin were synthesized and evaluated for their in vitro antibacterial activities. These pleuromutilin derivatives with substituted amino moiety exhibited excellent activities against methicillin-resistant Staphylococcus aureus, methicillin-resistant Staphylococcus epidermidis, Escherichia coli, and Streptococcus agalactiae. Compound 5b showed the highest antibacterial activities and even exceeded tiamulin. Moreover, the docking experiments provided information about the binding model between the synthesized compounds and peptidyl transferase center (PTC) of 23S rRNA.

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Scalable Synthesis of a Key Intermediate for the Production of Pleuromutilin-Based Antibiotics.

Project description:An improved synthesis of an eneimide, which is a useful precursor to pleuromutilin-based antibiotics, is reported. This synthesis proceeds in six steps and 17% overall yield (27% based on recovery of a key hydrindenone intermediate) and requires two fewer chromatography steps and five fewer days of reaction time than the previously reported route. The use of expensive, acutely toxic, and precious metal reagents or catalysts has been minimized.

| S-EPMC7001007 | biostudies-literature

Synthesis, biological activities and docking studies of pleuromutilin derivatives with piperazinyl urea linkage.

Project description:Antibiotics resistance is becoming increasingly common, involving almost all antibiotics on the market. Diseases caused by drug resistant bacteria, such as MRSA, have high mortality and negatively affect public health. The development of new drugs would be an effective means of solving this problem. Modifications based on bioactive natural products could greatly shorten drug development time and improve success rate. Pleuromutilin, a natural product from the basidiomycete bacterial species, is a promising antibiotic candidate. In this study, a series of novel pleuromutilin derivatives possessing piperazinyl urea linkage were efficiently synthesised, and their antibacterial activities and bactericidal properties were evaluated via MIC, MBC and Time-kill kinetics assays. The results showed that all compounds exhibited potent activities against tested strains, especially MRSA strains with MIC values as low as 0.125 μg/mL; 8 times lower than that of marketed antibiotic Tiamulin. Docking studies indicate substituted piperazinyl urea derivatives could provide hydrogen bonds and initiate π-π stacking between molecules and surrounding residues.

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Design and Synthesis of Pleuromutilin Derivatives as Antibacterial Agents Using Quantitative Structure-Activity Relationship Model.

Project description:The quantitative structure-activity relationship (QSAR) is one of the most popular methods for the virtual screening of new drug leads and optimization. Herein, we collected a dataset of 955 MIC values of pleuromutilin derivatives to construct a 2D-QSAR model with an accuracy of 80% and a 3D-QSAR model with a non-cross-validated correlation coefficient (r2) of 0.9836 and a cross-validated correlation coefficient (q2) of 0.7986. Based on the obtained QSAR models, we designed and synthesized pleuromutilin compounds 1 and 2 with thiol-functionalized side chains. Compound 1 displayed the highest antimicrobial activity against both Staphylococcus aureus ATCC 29213 (S. aureus) and Methicillin-resistant Staphylococcus aureus (MRSA), with minimum inhibitory concentrations (MICs) < 0.0625 μg/mL. These experimental results confirmed that the 2D and 3D-QSAR models displayed a high accuracy of the prediction function for the discovery of lead compounds from pleuromutilin derivatives.

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