Evaluation of substituted ebselen derivatives as potential trypanocidal agents

Abstract

Human African trypanosomiasis is a disease of sub-Saharan Africa, where millions are at risk for the illness. The disease, commonly referred to as African sleeping sickness, is caused by an infection by the eukaryotic pathogen, Trypanosoma brucei. Previously, a target-based high throughput screen revealed ebselen (EbSe), and its sulfur analog, EbS, to be potent in vitro inhibitors of the T. brucei hexokinase 1 (TbHK1). These molecules also exhibited potent trypanocidal activity in vivo. In this manuscript, we synthesized a series of sixteen EbSe and EbS derivatives bearing electron-withdrawing carboxylic acid and methyl ester functional groups, and evaluated the influence of these substituents on the biological efficacy of the parent scaffold. With the exception of one methyl ester derivative, these modifications ablated or blunted the potent TbHK1 inhibition of the parent scaffold. Nonetheless, a few of the methyl ester derivatives still exhibited trypanocidal effects with single-digit micromolar or high nanomolar EC50 values.

Recent Advances in the Synthesis of Heterocycles via Reactions Involving Elemental Sulfur

“…Previously, a similar reaction with bromo derivative 249 was studied in the presence of up to 50 mol % of copper catalyst and ligand 1,10-phenanthroline (Scheme 87). [109] It should be noted that the ester function could favor sulfur incorporation.…”

Synthesis of a Hybrid between SOD Mimetic and Ebselen to Target Oxidative Stress

“…The ring closure to form the isoselenazolone 2 was achieved in good yields by preparation of KSeO t Bu with selenium powder and potassium tert ‐butoxide in dimethylformamide to react with 1 . Quantitative hydrolysis of the ethyl ester was achieved with 5 equivalents of lithium hydroxide to yield ebselen acid ( 3 ) in a mixture of tetrahydrofuran, methanol and water . To activate the carboxylic acid function, N ‐hydroxysuccinimide in combination with 1‐ethyl‐3‐(3‐dimethylaminopropyl)carbodiimide hydrochloride (EDCxHCl) was used and extraction with water facilitated the removal of the urea by‐product .…”

“…in DMF, 60 °C, 48 h; (c) LiOH · H 2 O (5.0 equiv.) in THF/MeOH/H 2 O (2:1:1), r.t., 4 days, acidic workup; (d) N ‐hydroxysuccinimide (1.5 equiv.) and EDCxHCl (1.5 equiv.)…”

In vitro Anti-Trypanosomal Activities of Indanone-Based Chalcones

“…T.b. gambiense is solely common in west Africa and causes a chronic form of HAT [4,5], while T.b rhodesiense is endemic to east Africa and causes an acute form of HAT [6,7]. Both forms of the disease are fatal if not treated [8].…”