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Sonousi, A., and D. Crich, "Selective Protection of Secondary Amines as the N-Phenyltriazenes. Application to Aminoglycoside Antibiotics", Organic Letters, vol. 17, pp. 4006-4009, 2015.
Quirke, J. C. K., G. C. Sati, A. Sonousi, M. Gysin, K. Haldimann, E. C. Böttger, A. Vasella, S. N. Hobbie, and D. Crich, "Structure-Activity Relationships for 5′′ Modifications of 4,5-Aminoglycoside Antibiotics", ChemMedChem, vol. n/a, issue n/a: John Wiley & Sons, Ltd, pp. e202200120, 2022. AbstractWebsite

Abstract Modification at the 5??-position of 4,5-disubstituted aminoglycoside antibiotics (AGAs) to circumvent inactivation by aminoglycoside modifying enzymes (AMEs) is well known. Such modifications, however, unpredictably impact activity and affect target selectivity thereby hindering drug development. A survey of 5??-modifications of the 4,5-AGAs and the related 5-O-furanosyl apramycin derivatives is presented. In the neomycin and the apralog series, all modifications were well-tolerated, but other 4,5-AGAs require a hydrogen bonding group at the 5??-position for maintenance of antibacterial activity. The 5??-amino modification resulted in parent-like activity, but reduced selectivity against the human cytosolic decoding A site rendering this modification unfavorable in paromomycin, propylamycin, and ribostamycin. Installation of a 5??-formamido group and, to a lesser degree, a 5??-ureido group resulted in parent-like activity without loss of selectivity. These lessons will aid the design of next-generation AGAs capable of circumventing AME action while maintaining high antibacterial activity and target selectivity.

Sonousi, A., A. Vasella, and D. Crich, "Synthesis of a Pseudodisaccharide Suitable for Synthesis of Ring I Modified 4,5-2-Deoxystreptamine Type Aminoglycoside Antibiotics", The Journal of Organic Chemistry, vol. 85, issue 11: American Chemical Society, pp. 7583 - 7587, 2020. AbstractWebsite

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Sonousi, A., D. Shcherbakov, A. Vasella, E. C. Böttger, and D. Crich, "Synthesis, ribosomal selectivity, and antibacterial activity of netilmicin 4'-derivatives", MedChemComm, vol. 10, issue 6: Royal Society of Chemistry, pp. 946 - 950, 2019/04/25. AbstractWebsite

Halogenation of a suitably protected netilmicin derivative enables preparation of 4'-chloro-, bromo-, and iodo derivatives of netilmicin after deprotection. Suzuki coupling of a protected 4'-bromo derivative with phenylboronic acid or butyltrifluoroborate affords the corresponding 4'-phenyl and 4'-butyl derivatives of netilmicin. Sulfenylation of suitably protected netilmicin derivative with ethanesulfenyl chloride followed by deprotection affords 4'-ethylsulfanylnetilmicin. All netilmicin 4'-derivatives displayed reduced levels of inhibition for prokaryotic ribosomes and reduced antibacterial activity against typical Gram-positive and Gram-negative strains. None of the derivatives displayed enhanced target selectivity.

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