Natural products have extensively contributed toward the discovery of new leads for Alzheimer's disease. During our search for new inhibitors of cholinesterase enzymes from natural sources, the ethyl acetate (EtOAc) extract of Rumex abyssinicus Jacq was identified as a dual cholinesterase inhibitor with IC 50 values of 2.7 and 11.4 μg/mL against acetylcholinesterase (AChE) and butyrylcholinesterase (BChE), respectively. The phytochemical investigation of the EtOAc extract has resulted in isolation of four anthraquinones, namely, helminthosporin, emodin, chrysophanol, and physcion, amongst which the helminthosporin has been isolated for the first time from Rumex sp. All isolated secondary metabolites have displayed significant inhibition of EeAChE with IC 50 values of 2.63, 15.21, 33.7, and 12.16 μM, respectively. In addition, the helminthosporin was also found to inhibit BChE with an IC 50 value of 2.99 μM. The enzyme kinetic study has indicated that helminthosporin inhibits AChE and BChE in a noncompetitive manner with k i values of 10.3 and 12.3 μM, respectively. The results of molecular modeling and propidium iodide displacement assay have revealed that helminthosporin occupies the peripheral anionic site of the active site gorge of AChE. In the PAMPA-BBB permeability assay, helminthosporin was found to possess high BBB permeability (P e = 6.16 × 10 −6 cm/s). In a nutshell, helminthosporin has been identified as a brain permeable dual cholinesterase inhibitor, and thus its further synthetic exploration is warranted for optimization of its potency.
NLRP3 inflammasome is an important therapeutic target for a number of human diseases. Herein, computationally designed series of quinazolin-4(3H)-ones were synthesized using iodine-catalyzed coupling of arylalkynes (or styrenes) with O-aminobenzamides. The key event in this transformation involves the oxidative cleavage of the C−C triple/ double bond and the release of formaldehyde. The reaction relies on the C−N bond formation along with the C−C bond cleavage under metal-free conditions. The nitro-substituted quinazolin-4(3H)-one 2k inhibited NLRP3 inflammasome (IC 50 5 μM) via the suppression of IL-1β release from ATP-stimulated J774A.1 cells.
The overexpression of α-synuclein
(α-syn) and its aggregation
is the hallmark of Parkinson’s disease. The α-syn aggregation
results in the formation of Lewy bodies that causes neuronal cell
death. Therefore, the small molecules that can protect neuronal cells
from α-syn toxicity or inhibit the aggregation of α-syn
could emerge as anti-Parkinson agents. Herein, a library of methoxy-stilbenes
was screened for their ability to restore the cell growth from α-syn
toxicity, using a yeast strain that stably expresses two copies of
a chromosomally integrated human α-syn gene. Tetramethoxy-stilbene
4s
, a nonantioxidant, was the most capable of restoring cell
growth. It also rescues the more toxic cells that bear three copies
of wild-type or A53T-mutant α-syn, from cell growth block. Its
EC
50
values for growth restoration of the 2-copy wild-type
and the 3-copy mutant α-syn strains are 0.95 and 0.35 μM,
respectively. Stilbene
4s
mitigates mitochondrial membrane
potential loss, negates ROS production, and prevents nuclear DNA-fragmentation,
all hallmarks of apoptosis. However,
4s
does not rescue
cells from the death-inducing effects of Bax and βA4, which
suggest that
4s
specifically inhibits α-syn-mediated
toxicity in the yeast. Our results signify that simultaneous use of
multiple yeast-cell-based screens can facilitate revelation of compounds
that may have the potential for further investigation as anti-Parkinson’s
agents.
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