Design, Synthesis, and Structure−Activity Relationship of Indole-3-glyoxylamide Libraries Possessing Highly Potent Activity in a Cell Line Model of Prion Disease

Abstract

Transmissible spongiform encephalopathies (TSEs) are a family of invariably fatal neurodegenerative disorders for which no effective curative therapy currently exists. We report here the synthesis of a library of indole-3-glyoxylamides and their evaluation as potential antiprion agents. A number of compounds demonstrated submicromolar activity in a cell line model of prion disease together with a defined structure-activity relationship, permitting the design of more potent compounds that effected clearance of scrapie in the low nanomolar range. Thus, the indole-3-glyoxylamides described herein constitute ideal candidates to progress to further development as potential therapeutics for the family of human prion disorders.

Structure–Activity Relationship Refinement and Further Assessment of Indole‐3‐glyoxylamides as a Lead Series against Prion Disease

“…[6] Consecutive reaction of indole with oxalyl chloride followed by the appropriate psubstituted aniline provided the desired products in a twostep, one-pot procedure. During the latter step, 2,6-lutidine was employed as a base in the given examples as it had been found to give improved yields as compared to Hünig's base (N,N-diisopropylethylamine, DIPEA) in some cases.…”

“…Optimisations were carried out in vacuo, and electrostatic potential (ESP) surfaces were plotted using GaussView between the limits of À5.0 and + 5.0 atomic units. ESPs were generated for structures 1 a-k, 1 m and 1 o, together with a handful of additional examples from our previous report: [6] 1 q-v (where R 1 = piperidin-1-yl, SMe, OCF 3 , Me, OH and F, respectively). Since hydrogen-bond acceptor character of the psubstituent (R 1 position) had previously been postulated as important in contributing to activity, [6] the calculated ESPs were inspected for any obvious correlation between electronic properties and antiprion EC 50 values.…”

“…ESPs were generated for structures 1 a-k, 1 m and 1 o, together with a handful of additional examples from our previous report: [6] 1 q-v (where R 1 = piperidin-1-yl, SMe, OCF 3 , Me, OH and F, respectively). Since hydrogen-bond acceptor character of the psubstituent (R 1 position) had previously been postulated as important in contributing to activity, [6] the calculated ESPs were inspected for any obvious correlation between electronic properties and antiprion EC 50 values. Within the most interesting subset of compounds-those bearing an unsubstituted 5-membered ring at the key R 1 position-a qualitative relationship was seen between increasing EC 50 values and growing negative character of the glyoxylamide-linked aromatic ring ( Figure 3).…”

“…[6] The most active compounds displayed low nanomolar EC 50 values (Figure 1 a), and a general requirement was recognised for a psubstituted aniline moiety at the glyoxylamide position, ideally containing at least one hydrogen-bond acceptor. Substitution at the indole C-2 was not tolerated.…”

“…Hence, structures 1 c and 1 d were selected as parent compounds for these new libraries, together with the N-phenyl derivative (R 1 = H, EC 50 = 0.32 mm; [6] Figure 1 b), to represent a range of activities. Analogues of one inactive parent molecule, N-benzyl-2-(1H-indol-3-yl)-2-oxoacetamide, were also proposed, to ascertain whether any of the new modifications might be able to improve the performance of this compound.…”