(1152-A) Development of novel 9H-carbazole-4H-chromene molecular hybrids as multi-target directed ligands for the treatment of Alzheimer’s disease
Monday, February 5, 2024
12:00 PM – 1:00 PM EST
Location: Exhibit Halls AB
Abstract: Alzheimer’s disease (AD) is the neurodegenerative disease affecting mental ability and neurocognitive functions. Treating multifactorial conditions of AD with a single target-directed drug is highly difficult. Thus, there is an urgent need to develop novel multi-target directed ligands (MTDLs) as possible anti-AD drugs. Herein, we have designed and synthesized a series of 3-(4H-chromen-4-yl)-9H-carbazol-4-ols (1-18) through one-pot three-component reaction as MTDLs for the treatment of AD. Reaction involves substituted salicylaldehydes, (E)-N-methyl-1-(methylthio)-2-nitroethenamine and hydroxycarbazole with triethylamine as a catalyst in ethanol. The transformation involves the formation of carbazole-chromene hybrids by formation of two C-C bonds and one C-O bond in a single synthetic operation. Rapid one-pot reaction does not require chromatographic purification and proceeds under mild conditions with high synthetic yields. Synthesized and structurally characterised ligands were then in-vitro screened against both acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) enzymes. Most of the ligands have shown moderate to good cholinesterase inhibitory activity in in-vitro screening compared to standard drug. Two most active ligands have shown excellent anticholinesterase response against both enzymes (compound-3, IC50 = 1.59 µM, AChE and compound-9, IC50 = 1.34 µM, AChE; compound-3, IC50 = 3.98 µM, BuChE and compound-9, IC50 = 5.08 µM, BuChE). These results were then well validated through a detailed computational study. Both analogs have shown good thermodynamic behaviour and stability through interactions with characteristic amino acid residues throughout simulation of 100 ns against cholinesterase enzymes. Synthesized compounds were then investigated for antagonistic properties using an electrophysiological assay of N-methyl-D-aspartate receptors (NMDAR)-mediated cation currents at heterologically expressed recombinant GluN1-1a/GluN2A-D receptor subtypes. NMDAR channel-blocking activity was examined using two-electrode voltage clamp recordings in Xenopus laevis oocytes. We have identified three potential GluN1-1a + GluN2B-selective antagonists; namely, compound-3 (IC50 = 3.98 µM), compound-9 (IC50 = 7.19 µM), and compound-12 (IC50 = 4.62 µM). The effect of these three active analogs on autophagy regulation was determined using stably transfected SH-SY5Y neuroblastoma cells. Compound-3 significantly enhanced the autophagy flux in neuroblastoma cells. Most active ligand (compound-3) did not exhibit any acute toxicity symptoms in rats at doses up to 1000 mg/kg. Compound-3 significantly reversed scopolamine induced memory deficit in a mice model. Putting together, our findings evidently showed that the compound-3 is a potential MTDL and prototype candidate to develop more effective anti-AD drugs.