Disassembly of preformed amyloid beta fibrils by small organofluorine molecules

Abstract

A potential therapeutic approach for Alzheimer’s disease is to reduce the amount of toxic amyloid-beta oligomers and fibrillar amyloid plaques. In order to contribute to this approach the ability of small organofluorine compounds that were previously reported as successful inhibitors of fibrillogenesis to destabilize preformed fibrils of the amyloid-beta peptide was studied. These organofluorine molecules including chiral compounds were tested in vitro using standard methods based on Thioflavin-T (THT) fluorescence spectroscopy, atomic force microscopy (AFM) and Fourier-transform infrared spectroscopy (FTIR). It was observed that 5′-halogen substituted 3,3,3-trifluoromethyl-2-hydroxyl-(indol-3-yl)-propionic acid esters showed significant activity in the disassembly of the preformed fibrils. Since the same compounds were identified as strong fibrillogenesis inhibitors as well, this dual action makes them promising candidates for further drug development.

Sulfonamides as multifunctional agents for Alzheimer’s disease

“…In contrast, the long linear-shaped compounds (13-28) exhibited moderate to good fibrillogenesis inhibition. Compounds 14,18,19,21 and 26 showed the most significant effect (87%, 60%, 43%, 64% and 45%, respectively). To confirm that inhibition was not due to THT displacement by compounds during the above assays, complementary Atomic Force Microscopy (AFM) experiments were performed.…”

“…Interestingly, 27 and 28 showed 50-100% inhibition of oligomer formation. These compounds are similar to the long chain sulfonamides (13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26), however, they lack the sulfonamide moiety. Comparing the activity of the compounds in the two Ab self-assembly inhibition assays one cannot fail to notice that the behaviour of the compounds in the two assays are the opposite; a compound is either a fibril inhibitor or an oligomer inhibitor.…”

“…The small commercial sulfonamides and saccharin derivatives (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12) showed moderate inhibition (up to 54%, except 11) of oligomers while the long chain linker containing sulfonamides (13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26) were generally oligomer formation promoters. Interestingly, 27 and 28 showed 50-100% inhibition of oligomer formation.…”

“…16 There is a growing sentiment that multitarget therapeutics may combat the complex pathogenesis of the disease more effectively than single-target approaches. 17 Extending our recent efforts on the development of antiamyloidogenic compounds [18][19][20][21][22][23][24] we describe the synthesis, biochemical evaluation, and potential multifunctional application of sulfonamide-based small molecule agents, including saccharin, and other analogues. Sulfonamides exhibit a broad range of biological effects and are well-tolerated in biomedical applications.…”

“…This design aims to provide more flexibility to the compounds and at the same time to continue to have large flat end-units. The synthesis of these second generation compounds (14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26) is summarized in Scheme 2a.…”