Thiazolino 2-Pyridone Amide Inhibitors of Chlamydia trachomatis Infectivity

Abstract

The bacterial pathogen Chlamydia trachomatis is a global health burden currently treated with broad-spectrum antibiotics which disrupt commensal bacteria. We recently identified a compound through phenotypic screening that blocked infectivity of this intracellular pathogen without host cell toxicity (compound 1, KSK 120). Herein, we present the optimization of 1 to a class of thiazolino 2-pyridone amides that are highly efficacious (EC50 ≤ 100 nM) in attenuating infectivity across multiple serovars of C. trachomatis without host cell toxicity. The lead compound 21a exhibits reduced lipophilicity versus 1 and did not affect the growth or viability of representative commensal flora at 50 μM. In microscopy studies, a highly active fluorescent analogue 37 localized inside the parasitiphorous inclusion, indicative of a specific targeting of bacterial components. In summary, we present a class of small molecules to enable the development of specific treatments for C. trachomatis.

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

“…13) served as a key intermediate (Scheme 1). In our previous study 10 the phenyl amide and p-methyl phenyl amide at the C3-position gave similar biological results. We therefore prepared C8-methoxy, C3-amide analogues 5 and 6 by amide coupling under basic conditions with the corresponding amine and propylphosphonic anhydride as coupling reagent.…”

“…In this study, we have instead synthesized and evaluated a small library of C8-oxygen and nitrogen analogues with the overall aim to maintain anti-Chlamydial activity and improve oral availability. An earlier study 10 showed that there was no discernable difference between the two enantiomers of compound 24 and therefore all compounds presented here were prepared and tested as racemic mixtures.…”

“…9 Introduction of an amine substituent in the C6-position and saturation of the C2-C3 double bond resulted in compound 2, with higher activity and better physiochemical properties than its precursor. 10 Further development by exchanging the hydrolysable C3-phenyl amide to non-hydrolysable amide isosteres resulted in the potent 1,2,3-triazole analogue 3 (Fig. 1).…”

Synthesis and Evaluation of Antioxidant Activity of Some New Heterocyclic Compounds Bearing the Benzo[B]Furan Moiety

“…2-Pyridone derivatives are known to exhibit diverse biological activities (Good et al, 2016) in view of this herein the synthesis of some 2-pyridone derivatives via the reaction of compound 2 with certain nucleophilic reagents. Thus, when 2 was fused with acetylacetone in the presence of a catalytic amount of pipridine a cyclocondensation reaction smoothly afforded…”

TBHP-mediated highly efficient dehydrogenative cross-oxidative coupling of methylarenes with acetanilides

“…Recently, amides have attracted more and more attention due to their extensive utilization in pharmaceutical and agrochemical applications [1–3], as well as for precursors in organic synthesis for the construction of natural products, polymers and organic materials [4–6]. The database of medicinal chemistry indicates that around 25% of synthetic drugs contain the amide moiety [7].…”