Toward the Identification of Novel Antimicrobial Agents: One-Pot Synthesis of Lipophilic Conjugates of N-Alkyl d- and l-Iminosugars

Abstract

In the effort to improve the antimicrobial activity of iminosugars, we report the synthesis of lipophilic iminosugars 10a–b and 11a–b based on the one-pot conjugation of both enantiomeric forms of N-butyldeoxynojirimycin (NBDNJ) and N-nonyloxypentyldeoxynojirimycin (NPDNJ) with cholesterol and a succinic acid model linker. The conjugation reaction was tuned using the established PS-TPP/I2/ImH activating system, which provided the desired compounds in high yields (94–96%) by a one-pot procedure. The substantial increase in the lipophilicity of 10a–b and 11a–b is supposed to improve internalization within the bacterial cell, thereby potentially leading to enhanced antimicrobial properties. However, assays are currently hampered by solubility problems; therefore, alternative administration strategies will need to be devised.

N-Substituted l-Iminosugars for the Treatment of Sanfilippo Type B Syndrome

“…The PS-TPP/I 2 activating system (either in combination or without imidazole) has been already employed in many synthetic studies aimed to achieve different chemical transformations. ,, In this case, it can be employed in the absence of imidazole, thus allowing us to devise a synthetic procedure not requiring chromatographic purification. As a matter of fact, the resin-bound phosphine oxide, representing the sole reaction byproduct, can be simply filtered off and in this case recycled by reduction to the starting phosphine form …”

“…Overall, these findings suggest that iminosugars represent attractive drug candidates for the treatment of Sanfilippo disease and therefore further efforts should be devoted to identify novel iminosugars effective in reducing HS and lysosomal accumulation in Sanfilippo patients. In the frame of our previous studies on the role of chirality in the pharmacological activity of iminosugars and other bioactive compounds, − we recently highlighted the promising potential of unnatural l - gluco -configured iminosugars for the treatment of rare diseases. Particularly, l -NBDNJ ( ent - 2 , Figure ), the synthetic enantiomer of d -NBDNJ ( 2 ), showed an interesting potential for the treatment of Pompe lysosomal disease, while not acting as an inhibitor of the most common glycosidases, differently from its enantiomer .…”

Synthesis of Piperidine Nucleosides as Conformationally Restricted Immucillin Mimics

“…In the subsequent ketalization step of OH groups in 10 , we used an alternative procedure to the standard protocol (PTSA, 2,2-dimethoxypropane, 2-methoxypropene) [ 48 ], in order to avoid strictly anhydrous conditions, which are typically required to limit by-product formation derived from acid-catalysed oxirane ring opening. Exploiting our longstanding expertise in the field [ 23 , 49 , 50 , 51 , 52 , 53 ], we chose the procedure involving the use of polymer-supported triphenyl phosphine (PS-TPP)/I 2 /imidazole (ImH) system as the activating agent for the protection reaction, using acetone as the acetonide source. In this case, the reaction involves the activation of acetone by the triphenylphosphonium iodide and the subsequent double attack by the diol to the activated ketone.…”

The Glucocorticoid PYED-1 Disrupts Mature Biofilms of Candida spp. and Inhibits Hyphal Development in Candida albicans

“…As part of our interest in the synthesis of compounds endowed with pharmacological activity [ 8 , 9 , 10 , 11 , 12 ], we recently developed a novel synthetic route aimed at the preparation of the corticosteroid drug deflazacort (DFZ, Figure 1 ) in order to explore its antimicrobial activity.…”