Structure-activity relationships of bis(arylsulfonamide) N,N'-diacetic acid derivatives as direct inhibitors of Keap1-Nrf2 protein-protein interaction
Creators: name: Ali Sayed Ahmed, Ahmed R.
Publisher: name: No Publisher Supplied
Year: 2022

description: The Keap1-Nrf2-ARE signaling pathway controls transcription and expression of a variety of antioxidant cellular cytoprotective proteins and enzymes. Activation of this system plays a vital defensive role in preventing pathological conditions caused by oxidative stress and inflammation. Targeting Keap1–Nrf2 protein–protein interaction (PPI) has attracted a great deal of attention as a therapeutic strategy for a variety of oxidative stress-related conditions and inflammatory diseases including chronic obstructive pulmonary disease (COPD) and chronic kidney disease in addition to cancer chemoprevention. Several Keap1–Nrf2 PPI inhibitors have been reported including dimethyl fumarate as an FDA approved drug for the treatment of patients suffering from relapsing multiple sclerosis. To improve the cellular potency, metabolic stability or drug-likeness of direct inhibitors, we have focused our efforts in this work on discovering diverse classes of potent small molecule direct inhibitors based on known compounds via four different scaffolds. In first part of this study, we designed, synthesized, and evaluated a series of bis(arylsulfonamido)benzo[b]heterocycles-N,N’-diacetic acids with potential improvement in cellular efficacy and metabolic stability profiles. The SAR studies revealed that 7-halo-2,4-disubstituted benzothiophenes, 3,5-disubstituted benzothiophenes, and 2,3-unsubstituted benzothiophene/indoles exhibited potent inhibitory activity in the submicromolar or nanomolar range. Among them, compounds 109b, 113a, 113b, 217d, 228d, 235a, 234b, 243c, 251a, 251b, and 251h are the most promising noncovalent inhibitors, with single-digit nanomolar activity in a time-resolved fluorescence resonance energy transfer (TR-FRET) assay. In part II, we synthesized and evaluated a series of disubstituted o-xylylene derivatives with potential improvement in cellular efficacy and metabolic stability profiles. A preliminary SAR study was conducted on the four regions of the lead compound. Among the compounds synthesized, compound 291d showed the best activity in this series with an activity of 3.8 nM in the TR-FRET assay. Part III involved synthesis and evaluation of a series of 1,4-bis(arylsulfonamido)naphthalene-N,N’-diacetic acids scaffold with 2-styryl/acrylate/acrylamide fragments. Most of these compounds synthesized showed potent binding affinity to the Keap1 Kelch domain in the TR-FRET assay with IC₅₀ &lt;20 nM. Compounds 304a, 304b, and 317i (TR-FRET IC₅₀&lt; 2 nM) showed over 10-fold improvement in TR-FRET IC₅₀ value in comparison with the reference lead compound (LH762). Part IV included synthesis and evaluation of a series of 1,3-bis(arylsulfonamido)phenylene/naphthalene-N,N’-diacetic acid scaffolds containing 2-O-linked fragments with potential improvement in cellular efficacy and metabolic stability profiles. A SAR study was conducted on the sulfonamide and the O-linked substituent at the 2-position. Among the synthesized analogs, compounds 336d, 341b, and 341c were the three most active in this series with TR-FRET IC₅₀ value &lt;10 nM. The optimized new scaffolds represent promising starting points for further biological evaluation in cells and animal models for the development of these Nrf2 activators as potential clinical candidates.