Thiazolino 2-Pyridone Amide Isosteres As Inhibitors of Chlamydia trachomatis Infectivity

Abstract

Chlamydia trachomatis is a global health burden due to its prevalence as a sexually transmitted disease and as the causative agent of the eye infection trachoma. We recently discovered 3-amido thiazolino 2-pyridones which attenuated C. trachomatis infectivity without affecting host cell or commensal bacteria viability. We present here the synthesis and evaluation of nonhydrolyzable amide isosteres based on this class, leading to highly potent 1,2,3-triazole based infectivity inhibitors (EC ≤ 20 nM).

Methyl sulfonamide substituents improve the pharmacokinetic properties of bicyclic 2-pyridone basedChlamydia trachomatisinhibitors

“…We have previously prepared and tested 1,2,4-oxadiazole substituted compounds which are easily accessible directly from the corresponding carboxylic acids. 11 To further evaluate these moieties together with other C7-and C8substituents we prepared two more of these amide isosteres via hydrolysis of methyl ester 15 and then amide coupling with benzamide oxime and TBTU followed by cyclization 16 to generate the 1,2,4-oxadiazole 19. These analogues were C6aminated via the established nitration-reduction route resulting in four C6-amine analogues 20, 21, 22, and 23 (Scheme 3).…”

“…Reinfect values show inhibition of Chlamydia infectivity by the tested compound in relation to DMSO treated control infections. 10,11 The reinfect assay is cell based and also provides preliminary information about the abilities of the compounds to penetrate biological membranes, attach to their target and exert their function on the intracellular bacteria. In brief, HeLa cells infected with C. trachomatis serovar L2 were treated with a compound (2.5 μM or 1 μM) and incubated for 48 h before Chlamydia was harvested by cell lysis.…”

“…11 The ring-fused 2-pyridone analogues 2 and 3 inhibit Chlamydial infectivity (EC 50 < 60 nM) in a cell based assay without effecting host microbiota and showed no mutagenic potential when assessed with the Ames test. 11,12 Ideally a drug for the genital C. trachomatis infection would be administered orally. In vitro ADME (absorption, distribution, metabolism, excretion) testing regarding solubility and permeability was performed on 2 (not shown), yielding poor solubility and moderate permeability.…”

Durch sichtbares Licht vermittelte Synthese von β‐Chlorketonen aus Arylcyclopropanen

“…[8] Durch die Nutzung von Photoredoxkatalyse wollten wir überstçchiometrische Mengen an starken Lewis-Säuren sowie die Verwendung von Edelmetallen und vorfunktionalisierten Arylcyclopropanen vermeiden. Schließlich wurden bioaktive Verbindungen wie Derivate von Ciprofibrat, Tramadol und Bicyclo-2-pyridon [10] unter unseren Bedingungen umgesetzt. [9] Unter diesen Bedingungen beobachteten wir die Bildung von 53 %des gewünschten b-Chlorketons 2a (Tabelle 1, Eintrag 1).…”

Visible‐Light‐Mediated Synthesis of β‐Chloro Ketones from Aryl Cyclopropanes

“…In addition, different alkyl or aryl substituents gave moderate to excellent yields (2n-2p, 2r)a nd even ab oronic acid was well tolerated (2q). Fortunately,t hiophene derivatives could also be converted in moderate yields (2s, 2t), as well as the methyl-substituted aryl cyclopropane derivative 2u and the double-substituted aryl cyclopropane 2v.F inally,w es ubmitted bioactive compounds like derivatives of ciprofibrate,t ramadol, and ringfused 2-pyridones [10] to our reaction conditions.W hile the ciprofibrate derivative 2wcould only be obtained in low yield, which was probably due to facile decarboxylation of the alkyl carboxylic acid, the corresponding methyl ester as well as the tramadol derivative gave the products in high yields (2x-2y). Unfortunately,s ince 2-pyridones are known to react with oxygen under irradiation, only low yields were obtained in the case of ring-fused 2-pyridones (2z-2aa).…”