Design, synthesis and biological evaluation of novel naturally-inspired multifunctional molecules for the management of Alzheimer’s disease

Singh, Yash Pal; Tej, Gullanki Naga Venkata Charan; Pandey, Amruta; Priya, Khushbu; Pandey, Pankaj; Shankar, Gauri; Nayak, Prasant; Rai, Geeta; Chittiboyina, Amar G.; Doerksen, Robert J.; Vishwakarma, Swati; Modi, Gyan

doi:10.1016/j.ejmech.2020.112257

Cited by 51 publications

(65 citation statements)

References 51 publications

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“…The inhibitory activity for ChE was performed using the modified method of Ellman et al (1961) and following the previous work of , and Singh et al (2020). Cholinesterase (ChE) catalyzes the hydrolysis of acetylthiocholine iodide (ATCI) to produce the thiocholine and acetate, which reduces the 5,5-dithiobis-(2-nitrobenzoic acid) (DTNB) to yellow color product that can be detected colorimetrically at 415 nm.…”

Section: In Vitro Hache Inhibition Assaysmentioning

confidence: 99%

“…In clinical practice, it is well known that ChE inhibitors are an effective approach in improving the cognitive decline in AD. Thus, the inhibitory activities of the compounds (HCQ and RGZ) on hAChE were measured according to the modified Ellman method (Ellman et al, 1961) and following previous publications Singh et al, 2020). DZP, a well-known cholinesterase inhibitor available in the market for AD, was used as a reference drug.…”

Section: In Vitro Hache Inhibition Assaysmentioning

confidence: 99%

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Drug repurposing for Alzheimer’s disease: in silico and in vitro investigation of FDA-approved drugs as acetylcholinesterase inhibitors

Kumar

Gahlawat

Kumar

et al. 2020

Journal of Biomolecular Structure and Dynamics

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Section: In Vitro Hache Inhibition Assaysmentioning

confidence: 99%

Section: In Vitro Hache Inhibition Assaysmentioning

confidence: 99%

Drug repurposing for Alzheimer’s disease: in silico and in vitro investigation of FDA-approved drugs as acetylcholinesterase inhibitors

Kumar

Gahlawat

Kumar

et al. 2020

Journal of Biomolecular Structure and Dynamics

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“…Natural products (NPs) represent one of the major sources for the development of novel drugs for a variety of disorders, including neurodegenerative ones [ 20 , 21 ]. Drug development starting from NPs can be considered a highly challenging task given the NPs structural complexity, a number of chiral centers, laborious multi-step syntheses, and unfavorable ADMET properties [ 22 ].…”

Section: Introductionmentioning

confidence: 99%

Amaryllidaceae Alkaloids of Norbelladine-Type as Inspiration for Development of Highly Selective Butyrylcholinesterase Inhibitors: Synthesis, Biological Activity Evaluation, and Docking Studies

Mamun

Pidaný

Hulcová

et al. 2021

IJMS

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Alzheimer’s disease (AD) is a multifactorial neurodegenerative condition of the central nervous system (CNS) that is currently treated by cholinesterase inhibitors and the N-methyl-d-aspartate receptor antagonist, memantine. Emerging evidence strongly supports the relevance of targeting butyrylcholinesterase (BuChE) in the more advanced stages of AD. Within this study, we have generated a pilot series of compounds (1–20) structurally inspired from belladine-type Amaryllidaceae alkaloids, namely carltonine A and B, and evaluated their acetylcholinesterase (AChE) and BuChE inhibition properties. Some of the compounds exhibited intriguing inhibition activity for human BuChE (hBuChE), with a preference for BuChE over AChE. Seven compounds were found to possess a hBuChE inhibition profile, with IC50 values below 1 µM. The most potent one, compound 6, showed nanomolar range activity with an IC50 value of 72 nM and an excellent selectivity pattern over AChE, reaching a selectivity index of almost 1400. Compound 6 was further studied by enzyme kinetics, along with in-silico techniques, to reveal the mode of inhibition. The prediction of CNS availability estimates that all the compounds in this survey can pass through the blood-brain barrier (BBB), as disclosed by the BBB score.

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“…Heteroligand structures play an important role in biological processes [8][9][10][11], and model systems containing aromatic amines as the primary ligand and amino acid derivatives as the secondary ligand could be used to better understand the transport of metal ions and active substances through membranes and biochemical reactions catalyzed by metalloenzymes [12]. The aromatic properties improve the lipophilicity of the complexes [13], thus increasing the permeability through the cell wall [14]. However, to confirm the structure and stability of a particular heteroligand species, it is necessary to determine the interaction between two ligands bound to the same metal ion.…”

Section: Introductionmentioning

confidence: 99%

Chemical Characterization and Biological Evaluation of New Cobalt(II) Complexes with Bioactive Ligands, 2-Picolinehydroxamic Acid and Reduced Schiff Base N-(2-Hydroxybenzyl)alanine, in Terms of DNA Binding and Antimicrobial Activity

et al. 2021

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Five new heteroligand cobalt(II) complexes with 2-picolinehydroxamic acid and reduced Schiff base, N-(2-hydroxybenzyl)alanine, were formed in an aqueous solution over a wide pH range. The coordination properties of ligands towards the metal ion were determined using a pH-metric method, and then the speciation model was confirmed by UV–Vis studies. A stacking interaction between the Schiff base phenol ring and the 2-picolinehydroxamic acid pyridine ring was found to improve the stability of the heteroligand species, indicating more effective coordination in mixed-ligand complexes than in their respective binary systems. The antimicrobial properties of heteroligand complexes were determined against Gram-negative and Gram-positive bacteria, as well as fungal strains. The formulation demonstrated the highest bacteriostatic and bactericidal activity (3.65 mM) against two strains of Gram-negative Helicobacter pylori bacteria and towards Candida albicans and Candida glabrata; this is important due to the potential co-existence of these microorganisms in the gastric milieu and their role in the development of gastritis. The binary complexes in the cobalt(II)—2-picolinehydroxamic acid system and 2-picolinehydroxamic acid were not cytotoxic against L929 mouse fibroblasts, neither freshly prepared solutions or after two weeks’ storage. By comparison, the heteroligand complexes within the range 0.91–3.65 mM diminished the metabolic activity of L929 cells, which was correlated with increased damage to cell nuclei. The concentration of the heteroligand species increased over time; therefore, the complexes stored for two weeks exhibited stronger anticellular toxicity than the freshly prepared samples. The complexes formed in an aqueous solution under physiological pH effectively bound to calf thymus DNA in an intercalative manner. This DNA-binding ability may underpin the antimicrobial/antifungal activity of the heteroligand complexes and their ability to downregulate the growth of eukaryotic cells.

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Design, synthesis and biological evaluation of novel naturally-inspired multifunctional molecules for the management of Alzheimer’s disease

Cited by 51 publications

References 51 publications

Drug repurposing for Alzheimer’s disease: in silico and in vitro investigation of FDA-approved drugs as acetylcholinesterase inhibitors

Drug repurposing for Alzheimer’s disease: in silico and in vitro investigation of FDA-approved drugs as acetylcholinesterase inhibitors

Amaryllidaceae Alkaloids of Norbelladine-Type as Inspiration for Development of Highly Selective Butyrylcholinesterase Inhibitors: Synthesis, Biological Activity Evaluation, and Docking Studies

Chemical Characterization and Biological Evaluation of New Cobalt(II) Complexes with Bioactive Ligands, 2-Picolinehydroxamic Acid and Reduced Schiff Base N-(2-Hydroxybenzyl)alanine, in Terms of DNA Binding and Antimicrobial Activity

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