The multifaceted
nature of Alzheimer’s disease (AD) demands
treatment with multitarget-directed ligands (MTDLs) to confront the
key pathological aberrations. A novel series of triazinoindole derivatives
were designed and synthesized. In vitro studies revealed that all
the compounds showed moderate to good anticholinesterase activity;
the most active compound 23e showed an IC50 value of 0.56 ± 0.02 μM for AChE and an IC50 value of 1.17 ± 0.09 μM for BuChE. These derivatives
are also endowed with potent antioxidant activity. To understand the
plausible binding mode of the compound 23e, molecular
docking studies and molecular dynamics simulation studies were performed,
and the results indicated significant interactions of 23e within the active sites of AChE as well as BuChE. Compound 23e successfully diminished H2O2-induced
oxidative stress in SH-SY5Y cells and displayed excellent neuroprotective
activity against H2O2 as well as Aβ-induced
toxicity in SH-SY5Y cells in a concentration dependent manner. Furthermore,
it did not show any significant toxicity in neuronal SH-SY5Y cells
in the cytotoxicity assay. Compound 23e did not show
any acute toxicity in rats at doses up to 2000 mg/kg, and it significantly
reversed scopolamine-induced memory deficit in mice model. Additionally,
compound 23e showed notable in silico ADMET properties.
Taken collectively, these findings project compound 23e as a potential balanced MTDL in the evolution process of novel anti-AD
drugs.
The
Co
rona
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rus
D
isease (COVID-19) is caused because of novel coronavirus (SARS-CoV-2) pathogen detected in China for the first time, and from there it spread across the globe creating a worldwide pandemic of severe respiratory complications. The virus requires structural and non-structural proteins for its multiplication that are produced from polyproteins obtained by translation of its genomic RNA. These polyproteins are converted into structural and non-structural proteins mainly by the main protease (Mpro). A systematic screening of a drug library (having drugs and diagnostic agents which are approved by FDA or other world authorities) and the Asinex BioDesign library was carried out using pharmacophore and sequential conformational precision level filters using the Schrodinger Suite. From the screening of approved drug library, three antiviral agents ritonavir, nelfinavir and saquinavir were predicted to be the most potent Mpro inhibitors. Apart from these pralmorelin, iodixanol and iotrolan were also identified from the systematic screening. As iodixanol and iotrolan carry some limitations, structural modifications in them could lead to stable and safer antiviral agents. Screenings of Asinex BioDesign library resulted in 20 molecules exhibiting promising interactions with the target protein Mpro. They can broadly be categorized into four classes based on the nature of the scaffold, viz. disubstituted pyrazoles, cyclic amides, pyrrolidine-based compounds and miscellaneous derivatives. These could be used as potential molecules or hits for further drug development to obtain clinically useful therapeutic agents for the treatment of COVID-19.
Graphic abstract
Electronic supplementary material
The online version of this article (10.1007/s11030-020-10130-1) contains supplementary material, which is available to authorized users.
Tau
is a microtubule associated protein implicated in the pathogenesis
of several neurodegenerative diseases. Because of the channel forming
properties of other amyloid peptides, we employed planar lipid bilayers
and atomic force microscopy to test tau for its ability to form ion
permeable channels. Our results demonstrate that tau can form such
channels, but only under acidic conditions. The channels formed are
remarkably similar to amyloid peptide channels in their appearance,
physical and electrical size, permanence, lack of ion selectivity,
and multiple channel conductances. These channels differ from amyloid
channels in their voltage dependence and resistance to blockade by
zinc ion. These channels could explain tau’s pathologic role
in disease by lowering membrane potential, dysregulating calcium,
depolarizing mitochondria, or depleting energy stores. Tau might also
combine with amyloid beta peptides to form toxic channels.
Despite extensive structure-function analyses, the molecular mechanisms of normal
and pathological tau action remain poorly understood. How does the C-terminal
microtubule-binding region regulate microtubule dynamics and bundling? In what biophysical
form does tau transfer trans-synaptically from one neuron to another, promoting
neurodegeneration and dementia? Previous biochemical/biophysical work led to the
hypothesis that tau can dimerize via electrostatic interactions between two N-terminal
“projection domains” aligned in an anti-parallel fashion, generating a
multivalent complex capable of interacting with multiple tubulin subunits. We sought to
test this dimerization model directly. Native gel analyses of full-length tau and deletion
constructs demonstrate that the N-terminal region leads to multiple bands, consistent with
oligomerization. Ferguson analyses of native gels indicate that an N-terminal fragment
(tau45-230) assembles into heptamers/octamers. Ferguson analyses of
denaturing gels demonstrates that tau45-230 can dimerize even in SDS. AFM
reveals multiple levels of oligomerization by both full-length tau and
tau45-230. Finally, ion-mobility mass spectroscopic analyses of
tau106-144, a small peptide containing the core of the hypothesized
dimerization region, also demonstrate oligomerization. Thus, multiple independent
strategies demonstrate that the N-terminal region of tau can mediate higher-order
oligomerization, which may have important implications for both normal and pathological
tau action.
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 Aβ1–42 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 Aβ1–42-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.
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