Carbazole-based semicarbazones and hydrazones as multifunctional anti-Alzheimer agents.

With the aim to combat a multi-faceted neurodegenerative Alzheimer's disease (AD), a series of carbazole-based semicarbazide and hydrazide derivatives were designed, synthesized and assessed for their cholinesterase (ChE) inhibitory, antioxidant and biometal chelating activity. Among them, (E)-2-((9-ethyl-9H-carbazol-3-yl)methylene)-N-(pyridin-2-yl)hydrazinecarbothioamide (62) and (E)-2-((9-ethyl-9H-carbazol-3-yl)methylene)-N-(5-chloropyridin-2-yl)hydrazinecarbothioamide (63) emerged as the premier candidates with good ChE inhibitory activities (IC50 values of 1.37 µM and 1.18 µM for hAChE, IC50 values of 2.69 µM and 3.31 µM for EqBuChE, respectively). All the test compounds displayed excellent antioxidant activity (reduction percentage of DPPH values for compounds (62) and (63) were 85.67% and 84.49%, respectively at 100 µM concentration). Compounds (62) and (63) conferred specific copper ion chelating property in metal chelation study. Molecular docking studies of compounds (62) and (63) indicate strong interactions within the active sites of both the ChE enzymes. Besides that, these compounds also exhibited significant in silico drug-like pharmacokinetic properties. Thus, taken together, they can serve as a starting point in the designing of multifunctional ligands in pursuit of potential anti-AD agents that might further prevent the progression of ADs.Communicated by Ramaswamy H. Sarma.

Further Studies on Triazinoindoles as Potential Novel Multitarget-Directed Anti-Alzheimer's Agents.

The inadequate clinical efficacy of the present anti-Alzheimer's disease (AD) drugs and their low impact on the progression of Alzheimer's disease in patients have revised the research focus from single targets to multitarget-directed ligands. A novel series of substituted triazinoindole derivatives were obtained by introducing various substituents on the indole ring for the development of multitarget-directed ligands as anti-AD agents. The experimental data indicated that some of these compounds exhibited significant anti-AD properties. Among them, 8-(piperidin-1-yl)-N-(6-(pyrrolidin-1-yl)hexyl)-5H-[1,2,4]triazino[5,6-b]indol-3-amine (60), the most potent cholinesterase inhibitor (AChE, IC50 value of 0.32 µM; BuChE, IC50 value of 0.21 µM), was also found to possess significant self-mediated Aß1-42 aggregation inhibitory activity (54% at 25 µM concentration). Additionally, compound 60 showed strong antioxidant activity. In the PAMPA assay, compound 60 exhibited blood-brain barrier penetrating ability. An acute toxicity study in rats demonstrated no sign of toxicity at doses up to 2000 mg/kg. Furthermore, compound 60 significantly restored the cognitive deficits in the scopolamine-induced mice model and Aß1-42-induced rat model. In the in silico ADMET prediction studies, the compound satisfied all the parameters of CNS acting drugs. These results highlighted the potential of compound 60 to be a promising multitarget-directed ligand for the development of potential anti-AD drugs.

Novel carbazole-stilbene hybrids as multifunctional anti-Alzheimer agents.

Molecules capable of engaging with multiple targets associated with pathological condition of Alzheimer's disease have proved to be potential anti-Alzheimer's agents. In our goal to develop multitarget-directed ligands for the treatment of Alzheimer's disease, a novel series of carbazole-based stilbene derivatives were designed by the fusion of carbazole ring with stilbene scaffold. The designed compounds were synthesized and evaluated for their anti-AD activities including cholinesterase inhibition, Aß aggregation inhibition, antioxidant and metal chelation properties. Amongst them, (E)-1-(4-(2-(9-ethyl-9H-carbazol-3-yl)vinyl)phenyl)-3-(2-(pyrrolidin-1-yl)ethyl)thiourea (50) appeared to be the best candidate with good inhibitory activities against AChE (IC50 value of 2.64 µM) and BuChE (IC50 value of 1.29 µM), and significant inhibition of self-mediated Aß1-42 aggregation (51.29% at 25 µM concentration). The metal chelation study showed that compound (50) possessed specific copper ion chelating property. Additionally, compound (50) exhibited moderate antioxidant activity. To understand the binding mode of 50, molecular docking studies were performed, and the results indicated strong non-covalent interactions of 50 with the enzymes in the active sites of AChE, BuChE as well as of the Aß1-42 peptide. Additionally, it showed promising in silico ADMET properties. Putting together, these findings evidently showed compound (50) as a potential multitarget-directed ligand in the course of developing novel anti-AD drugs.