New N-(4-(chlorodifluoromethoxy)phenyl)-1H-pyrrolo[2,3-b]pyridine-5-carboxamide derivatives were designed, synthesised, and evaluated as potential anticancer agents. Among the synthesised derivatives, compound 9c showed the highest potency against BCR-ABL1-positive K562 leukemia cells, with an IC50 of 0.26 ± 0.029 µM, followed by 9a (0.50 ± 0.005 µM), 9k (0.64 ± 0.075 µM) and 9l (0.69 ± 0.11 µM). Importantly, compounds 9a, 9c and 9k showed selectivity for leukemia cells and low toxicity to normal fibroblasts (IC50 > 50 µM), with selectivity indices of 100–192. Docking analysis showed that the designed analogues preserved the key pharmacophoric interactions of Asciminib, with compound 9k showing the best docking score (−42.07 kcal mol−1), followed by 9a (−40.44 kcal mol−1), compared with Asciminib (−40.13 kcal mol−1). Taken together, these results suggest that the N-(4-(chlorodifluoromethoxy)phenyl)-1H-pyrrolo[2,3-b]pyridine-5-carboxamide scaffold is a useful template for designing selective BCR-ABL1-directed anticancer agents, with compound 9c as an encouraging lead for further optimisation and mechanistic studies.
Pradeep B. Bhise, Sandeep B. Bhise, Somnath Dasgupta et al.· RSC Advances· 0 citations
Alzheimer’s disease (AD) is a complex neurodegenerative disorder characterized by the accumulation and aggregation of β-amyloid (Aβ) and chronic neuroinflammation mediated by the receptor for advanced glycation end products (RAGE). Current therapeutic candidates targeting RAGE signaling or Aβ aggregation continue to face challenges, including off-target toxicity, poor blood-brain barrier (BBB) penetration, and limited multi-target efficacy.
Naringenin (NAR), a naturally occurring flavanone polyphenol prioritized through structure-based virtual screening and preliminary biological evaluation, was selected for further mechanistic investigation as a potential dual-target modulator of RAGE-associated inflammatory signaling and Aβ42 fibrillization.
Molecular docking analyses showed that NAR interacts with the RAGE interface (PDB: 6XQ3) via π-cation interactions with ARG_98 and LYS_110 (docking score: −5.072 kcal/mol). At the Aβ fibril (PDB: 2MXU), NAR showed a superior docking score than ALZ-801 (valiltramiprosate), involving hydrogen bonding and π–π stacking with HIS_A14 (docking score: −8.098 kcal/mol). 100 ns molecular dynamics simulations supported the stability of these binding modes, with RMSD and RMSF values within acceptable ranges. MM-GBSA rescoring indicated competitive predicted binding free energies (ΔGBind: −30.260 kcal/mol at RAGE; −220.162 kcal/mol at the fibril, compared to ALZ- 801’s −214.482 kcal/mol), influenced by electrostatic and hydrophobic interactions. Per-residue energy decomposition indicated PHE_20 (−9.10 kcal/ mol) as the dominant hotspot residue, alongside ARG_98 (−4.71 kcal/mol) and LYS_52 (−3.96 kcal/mol) as key RAGE anchors.
In silico
ADMET profiling suggested favorable predicted BBB accessibility (score: 0.001), Caco-2 permeability, Lipinski compliance, and a more favorable predicted cardiac safety profile (hERG: 0.145) relative to V6Y. Experimentally, NAR reduced Aβ42-induced NF-κB activation in RAGE-positive C6 cells, protected SH-SY5Y neurons from Aβ42 toxicity, and inhibited Aβ42 fibrillization
in vitro
, producing non-seeding aggregates consistent with impaired fibril formation, and attenuated rotenone-induced α-synuclein-associated cellular stress.
Collectively, these findings support further investigation of NAR as a mechanistically plausible multi-target candidate for protein aggregation and RAGE-associated inflammatory signaling in neurodegenerative disease models.
Inderjeet Bhogal, I. Frydrych, Ajay Modi et al.· Frontiers in Pharmacology· 0 citations
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