Synthesis and pharmacological evaluation of nucleoside prodrugs designed to target siderophore biosynthesis in Mycobacterium tuberculosis

Abstract

The nucleoside antibiotic, 5′-O-[N-(salicyl)sulfamoyl]adenosine (1), possesses potent whole-cell activity against Mycobacterium tuberculosis (Mtb), the etiological agent of tuberculosis (TB). This compound is also active in vivo, but suffers from poor drug disposition properties that result in poor bioavailability and rapid clearance. The synthesis and evaluation of a systematic series of lipophilic ester prodrugs containing linear and α-branched alkanoyl groups from two to twelve carbons at the 3′-position of a 2′-fluorinated analogue of 1 is reported with the goal to improve oral bioavailability. The prodrugs were stable in simulated gastric fluid (pH 1.2) and under physiological conditions (pH 7.4). The prodrugs were also remarkably stable in mouse, rat, and human serum (relative serum stability: human~rat>>mouse) displaying a parabolic trend in the SAR with hydrolysis rates increasing with chain length up to eight carbons (t1/2 = 1.6 h for octanoyl prodrug 7 in mouse serum) and then decreasing again with higher chain lengths. The permeability of the prodrugs was also assessed in a Caco-2 cell transwell model. All of the prodrugs were found to have reduced permeation in the apical-to-basolateral direction and enhanced permeation in the basolateral-to-apical direction relative to the parent compound 2, resulting in efflux ratios 5–28 times greater than 2. Additionally, Caco-2 cells were found to hydrolyze the prodrugs with SAR mirroring the serum stability results and a preference for hydrolysis on the apical side. Taken together, these results suggest that the described prodrug strategy will lead to lower than expected oral bioavailability of 2 and highlight the contribution of intestinal esterases for prodrug hydrolysis.

Chemical and Biological Aspects of Nutritional Immunity—Perspectives for New Anti‐Infectives that Target Iron Uptake Systems

“…[40] They again concluded that C2'-fluorination (R 4 )w as the most successful modification, with activity maintained against MbtA whilst improving the PK properties.E nhancement of the lipophilicity and prodrug approaches,f or example,e ster prodrugs of C2'fluorosulfamide isostere 21 versus parent compound 20 led to inferior PK data (plasma stability at t 1/2 typically lower than that of 20). [41] An inherent limitation of 17 is degradation through the formation of cyclonucleosides. [42] Although this does not occur in 8-aza-3-deaza-adenines (e.g.…”

Chemische und biologische Aspekte von “Nutritional Immunity” – Perspektiven für neue Antiinfektiva mit Fokus auf bakterielle Eisenaufnahmesysteme

“…In den neuesten Ansätzen wurden von Aldrich und Mitarbeitern 2'-u nd 3'-Fluor-Analoga zu einem Sulfamid-Isoster 18 [39] synthetisiert, wobei die Zucker den "nçrdlichen" (C3'-endo,C 2 '-exo)o der "südlichen" (C2'-endo,C3'-exo)T eil einnehmen (Abbildung 6). [41] Eine inhärente Einschränkung von 17 ist der Abbau über die Bildung eines Cyclonucleosides. Die Erhçhung der Lipophilie oder Prodrug-Ansätze,w ie Estervorstufen des C2'-Fluorsulfonamid-Isosters 21 im Vergleich zur ursprünglichen Substanz 20 verschlechterten die PK-Eigenschaften (Plasmastabilitätw urde geringer).…”

“…Die Erhçhung der Lipophilie oder Prodrug-Ansätze,w ie Estervorstufen des C2'-Fluorsulfonamid-Isosters 21 im Vergleich zur ursprünglichen Substanz 20 verschlechterten die PK-Eigenschaften (Plasmastabilitätw urde geringer). [41] Eine inhärente Einschränkung von 17 ist der Abbau über die Bildung eines Cyclonucleosides. [42] Obwohl dies bei den 8-Aza-3-deaza-Adeninen (z.…”

“…Aufsätze den Derivaten von 2-Benzamidobenzoesäure (38,I C 50 PqsD = 1.2 mm), [63] 5-Aryl-Ureidothiophen-2-carbonsäure (39,I C 50 PqsD = 6 mm) [64] und von Indolen (40)(41)(42). Letztere inhibierten in P. aeruginosa die Bildung von 28 b,P yocyanin (35), Pyoverdin und Rhamnolipiden.…”

Novel 5′-Norcarbocyclic Pyrimidine Derivatives as Antibacterial Agents

“…Nucleoside derivatives have historically served as potent antiviral and anticancer agents [3], but it was not until 2000 that their anti-TB activity was reported [4]. Recently, several reports of modified nucleosides showing activity against Mycobacterium tuberculosis (M. tuberculosis) , Mycobacterium bovis (M. bovis) and Mycobacterium avium (M. avium) were published [4,5,6,7,8,9,10,11,12,13,14,15,16,17,18]. Among them, the best activity was observed for several uridine analogues (MIC 90 1 to 10 µg/mL) possessing 5-alkynyl (decynyl, dodecynyl, tetradecynyl, pyridylethynyl, etc.)…”