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

Autor: Patel DV; Faculty of Pharmacy, Kalabhavan Campus, The Maharaja Sayajirao University of Baroda, Vadodara 390001, Gujarat, India., Patel NR; Faculty of Pharmacy, Kalabhavan Campus, The Maharaja Sayajirao University of Baroda, Vadodara 390001, Gujarat, India., Kanhed AM; Shobhaben Pratapbhai Patel - School of Pharmacy & Technology Management, SVKM's NMIMS University, Vile Parle, Mumbai 400056, India., Teli DM; Department of Pharmaceutical Chemistry, L. M. College of Pharmacy, Navrangpura, Ahmedabad 380009, Gujarat, India., Patel KB; Faculty of Pharmacy, Kalabhavan Campus, The Maharaja Sayajirao University of Baroda, Vadodara 390001, Gujarat, India., Joshi PD; Faculty of Pharmacy, Kalabhavan Campus, The Maharaja Sayajirao University of Baroda, Vadodara 390001, Gujarat, India., Patel SP; Faculty of Pharmacy, Kalabhavan Campus, The Maharaja Sayajirao University of Baroda, Vadodara 390001, Gujarat, India., Gandhi PM; Faculty of Pharmacy, Kalabhavan Campus, The Maharaja Sayajirao University of Baroda, Vadodara 390001, Gujarat, India., Chaudhary BN; Faculty of Pharmacy, Kalabhavan Campus, The Maharaja Sayajirao University of Baroda, Vadodara 390001, Gujarat, India., Prajapati NK; Faculty of Pharmacy, Kalabhavan Campus, The Maharaja Sayajirao University of Baroda, Vadodara 390001, Gujarat, India., Patel KV; Faculty of Pharmacy, Kalabhavan Campus, The Maharaja Sayajirao University of Baroda, Vadodara 390001, Gujarat, India., Yadav MR; Faculty of Pharmacy, Kalabhavan Campus, The Maharaja Sayajirao University of Baroda, Vadodara 390001, Gujarat, India. Electronic address: mryadav11@yahoo.co.in.
Jazyk: angličtina
Zdroj: Bioorganic chemistry [Bioorg Chem] 2020 Aug; Vol. 101, pp. 103977. Date of Electronic Publication: 2020 May 26.
DOI: 10.1016/j.bioorg.2020.103977
Abstrakt: 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, Aβ 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 (IC 50 value of 2.64 μM) and BuChE (IC 50 value of 1.29 μM), and significant inhibition of self-mediated Aβ 1-42 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 Aβ 1-42 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.
Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
(Copyright © 2020 Elsevier Inc. All rights reserved.)
Databáze: MEDLINE
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