biostudies-literatureFortin JSNIA NIH HHSPurdue UniversityNINDS NIH HHSNational Institutes of HealthPharmaceutical Research and Manufacturers of America Foundation133574https://www.ebi.ac.uk/biostudies/studies/S-EPMC9614895biostudies-literatureUnknown1267In contrast to A<i>β</i> plaques, the spatiotemporal distribution of neurofibrillary tangles of hyperphosphorylated tau (p-tau) predicts cognitive impairment in Alzheimer's disease (AD), underscoring the key pathological role of p-tau and the utmost need to develop AD therapeutics centering upon the control of p-tau aggregation and cytotoxicity. Our drug discovery program is focused on compounds that prevent the aggregation and cytotoxicity of p-tau moieties of the tau isoform 1N4R due to its prevalence (1 N) and long-distance trans-synaptic propagation (4R). We prepared and tested twenty-four newly synthesized small molecules representing the urea (<b>1, 2, 3</b>), sulfonylurea (<b>4</b>), and sulfonamide (<b>5-24</b>) series and evaluated their anti-aggregation effects with biophysical mJournal of molecular structureAnti-fibrillization effects of sulfonamide derivatives on <i>α</i>-synuclein and hyperphosphorylated tau isoform 1N4R.PMC9614895R21AG070447-01A1R21 NS121826K08 AG071985P01 AG014449NS121826NS099328P01AG014449R01 NS099328R21 AG070447R44 AG057274R01 AG062435R01 AG060731R01AG060731R01AG062435730313R44AG57274Borhan BLiu MWang KWMaity SKuo MHFortin JSSaraswati APHagar HTShimanaka KDettmer UEllsworth EGanegamage SKCounts SEfalseAnti-fibrillization effects of sulfonamide derivatives on <i>α</i>-synuclein and hyperphosphorylated tau isoform 1N4R.In contrast to A<i>β</i> plaques, the spatiotemporal distribution of neurofibrillary tangles of hyperphosphorylated tau (p-tau) predicts cognitive impairment in Alzheimer's disease (AD), underscoring the key pathological role of p-tau and the utmost need to develop AD therapeutics centering upon the control of p-tau aggregation and cytotoxicity. Our drug discovery program is focused on compounds that prevent the aggregation and cytotoxicity of p-tau moieties of the tau isoform 1N4R due to its prevalence (1 N) and long-distance trans-synaptic propagation (4R). We prepared and tested twenty-four newly synthesized small molecules representing the urea (<b>1, 2, 3</b>), sulfonylurea (<b>4</b>), and sulfonamide (<b>5-24</b>) series and evaluated their anti-aggregation effects with biophysical m2022-01-01T00:00:00Z2022 Nov2026-05-27T12:06:29.566Z2024-11-08T20:15:57.446ZS-EPMC96148953631092210.1016/j.molstruc.2022.133574