Synthesis and Biological Evaluation of 8-Aminomethyltetracycline Derivatives as Novel Antibacterial Agents

Abstract

The C-8 position of the tetracyclines has been largely underexplored because of limitations in traditional semisynthetic techniques. Employing a total synthetic approach allowed for modifications at the C-7 and C-8 positions, enabling the generation of structure-activity relationships for overcoming the two most common tetracycline bacterial-resistance mechanisms: ribosomal protection (tet(M)) and efflux (tet(A)). Ultimately, several compounds were identified with balanced activity against both Gram-positive and Gram-negative bacteria, including pathogens bearing both types of tetracycline-resistance mechanisms. Compounds were screened in a murine systemic infection model to rapidly identify compounds with oral bioavailability, leading to the discovery of several compounds that exhibited efficacy when administered orally in murine pyelonephritis and pneumonia models.

Heterocyclyl Tetracyclines. 1. 7-Trifluoromethyl-8-Pyrrolidinyltetracyclines: Potent, Broad Spectrum Antibacterial Agents with Enhanced Activity against Pseudomonas aeruginosa

“…Compound 6 was readily prepared in quantitative yield by benzylation of phenol 5. 21 A Suzuki coupling 27 of aryl bromide 6 with N-Boc-2-pyrroleboronic acid catalyzed by dichloro[1,1′-bis-(diphenylphosphino)ferrocene] palladium (II) dichloromethane adduct gave compound 7 in 60% yield. Reduction of the pyrrole by catalytic hydrogenation at atmospheric pressure proceeded with concurrent removal of the benzyl protecting group.…”

“…Likewise, replacing the alkyl heterocyclic substitution at C8 with an aromatic heterocycle (compounds 30 and 31) further diminished potency, especially against the Gram-negative isolates, most likely due to the decreased basicity of the aromatic nitrogen. 21,24 We then fixed the C8 substituent as a 2-pyrrolidine ring and investigated the structure−activity relationships (SAR) of analogues with a range of substituents at C7 (R 7 ), as well as with various substitutions on the pyrrolidine ring at C8. As shown in Table 2, when R 7 was trifluoromethyl and the C8 pyrrolidine was not substituted, the diastereomer with a (2S)configured pyrrolidine (compound 43c) was 2-to greater than 64-fold more potent than the corresponding (2R)-configured diastereomer (compound 43d) against P. aeruginosa PA555 and all Gram-positive strains tested.…”

“…Purification of the residue by Biotage flash chromatography gave 15 as a white solid (412 mg, 32%). Phenyl 6-(Benzyloxy)-3-chloro-2-methyl-4-(piperidin-2-yl)benzoate (21). To the solution of compound 19 (437 mg, 1.01 mmol, 1 equiv) in methanol (2 mL) was added NaBH 4 (43 mg, 1.1 mmol, 1.1 equiv) at 0 °C.…”

“…Examples of this include minocycline ( 2 ) , and tigecycline ( 3 ). − While a few total synthesis routes have been developed successfully, most were lengthy as well as low overall yielding and therefore were impractical to scale both in terms of the number and quantity of new tetracycline analogues . A more recent total synthesis methodology developed by Myers and co-workers , and expanded by Tetraphase Pharmaceuticals has enabled the efficient introduction of a broad array of substituents at many more positions including C4, C4a, C5, C5a, C6, C7, C8, C9, and C12a, − as well as the incorporation of heterocyclic and polycyclic ring systems into the tetracycline core structure, − creating completely novel tetracycline derivatives that were previously inaccessible (or extremely difficult to access) through semisynthesis. More than 3000 tetracycline analogues have been synthesized by Tetraphase using the total synthesis approach.…”

Trifluoromethyl nitrogen heterocycles: synthetic aspects and potential biological targets

“…27). 96 Following the same principle, fluorinated cholesteryl ester transfer protein inhibitors 154 97 and antibacterial 8-aminomethyltetracycline derivative 155 98 were synthesized and their biological activities were subsequently evaluated (Fig. 28).…”