Solution-Phase Parallel Synthesis of a 1140-Member Ureidothiophene Carboxylic Acid Library

Abstract

A 1140-library of thiophene ureidoacids was synthesized by the reaction of a set of 60 primary or secondary amines with a number of 19 thieno[3,2-d]- or thieno[2,3-d][1,3]oxazine-2,4-diones. All compounds were obtained by a simple solution-phase combinatorial strategy on a 200-400-mg scale with over 70% yields and purities over 80%. Sixty library members chosen at random were successfully characterized by standard 1H NMR, HPLC/MS, and IR studies. Analgesic, antalgic, and antiinflammatory potential were investigated. The 1140-member ureidothiophene carboxylic acid library will be used in high-throughput screening assays.

Structure-Guided Optimization of Small-Molecule Folate Uptake Inhibitors Targeting the Energy-Coupling Factor Transporters

“…20,21 Final conversion with a variety of amines gave rise to the 5-aryl-3ureidothiophene-2-carboxylic acids 22-23, 25-32 in good yield. 17,18,22 Scheme 1: Synthesis of 5-aryl-3-ureidothiophene-2-carboxylic acids 22-23, 25-32. Reagents and conditions: a) i) POCl3, DMF, 50 °C to rt, ii) NH2OH•HCl, up to 150 °C, 75-90%.…”

Expanding the scaffold for bacterial RNA polymerase inhibitors: design, synthesis and structure–activity relationships of ureido-heterocyclic-carboxylic acids

“…The latter reacted with the appropriate amines in water followed by acidic workup to yield the desired 5-aryl-3-ureidothiophene-2-carboxylic acids 6–11 . 17,20,21 The compounds of classes II and III were synthesized by a straightforward procedures via Gewald reaction of the arylacetaldehydes 12a,b or the acetophenones 1a,b (Scheme 1) with ethyl cyanoacetate and elemental sulfur under basic conditions in a one-pot reaction to afford the ethyl esters 13a,b and 22a,b 22,23 respectively. After saponification, synthesis of both the 5- and 4-aryl-2-ureidothiophene-3-carboxylic acids 16–21 and 25–30 via the thiaisatoic anhydrides 15a,b and 24a,b was also successfully employed as described for the class I derivatives.…”

Exploring the chemical space of ureidothiophene-2-carboxylic acids as inhibitors of the quorum sensing enzyme PqsD from Pseudomonas aeruginosa

“…The esters (II) were then hydrolysed under basic conditions to afford the thiophene anthranilic acids (III) which were converted into the thiaisatoic anhydrides (IV) [32,33]. The anhydrides (IV) were reacted with various amines giving rise to the 5-aryl-3-ureidothiophene-2-carboxylic acids (V) [34]. Further substituents at the 5-aryl ring were introduced using boronic acids or esters, respectively, via Suzuki coupling yielding VI [35].…”