Sushant Kumar Shrivastava

A Pd(OAc) ₂ - catalyzed strategy for synthesizing cinnamic esters and acids from acrylic anhydride and aryl diazonium salts under mild conditions has been developed, which shows good tolerance towards a wide range of substrates.

The present study utilized a drug repurposing approach to identify potential GPVI receptor antagonists among FDA-approved drugs. Computational and molecular dynamics simulations revealed that adapalene and ranolazine exhibit strong binding affinities to GPVI receptors and stabilize GPVI proteins, respectively. Both compounds inhibited collagen-induced platelet aggregation, evidenced by the suppression of Syk tyrosine kinase expression, a marker of platelet activation, via GPVI stimulation, as confirmed through flow cytometry analysis. Further analysis using circular dichroism and Raman spectroscopy indicated that collagen exposure induced conformational changes in the α-helical domains of platelets, which were stabilized upon treatment with adapalene and ranolazine. Moreover, thrombotic events can lead to cerebral cell death due to hypoxia, which may be mitigated by neuroprotective compounds. Adapalene and ranolazine were assessed for their neuroprotective capabilities. The results showed that these compounds exhibited neuroprotective effects in SHSY5Y neuroblastoma cells subjected to oxygen–glucose deprivation/reperfusion (OGD/R) injury, reducing HIF-1α expression, ROS production, lipid peroxidation, and caspase-3 levels, while also improving mitochondrial membrane potential and glutathione levels. Acridine orange and propidium iodide staining studies further confirmed a decrease in apoptosis. In the FeCl₃-induced carotid artery thrombosis model, ranolazine effectively inhibited platelet aggregation by modulating GPVI receptor activity, reducing intracellular calcium levels, and enhancing cAMP signaling. It also suppressed critical platelet activation mediators, including COX-1, TXB₂, and PGE₂, thereby mitigating thrombus formation. Collectively, these results suggest that adapalene and ranolazine may serve as multimodal therapeutic agents with the potential to treat both thrombotic and neurological diseases. Future studies focusing on the adapalene and ranolazine molecular mechanisms, bleeding risk, dose titration, and long-term safety while managing thrombotic disorders have to be investigated.

Alzheimer’s disease (AD) is a multifactorial and emerging neurological disorder, which has invoked researchers to develop multitargeted ligands. Herein, hybrid conjugates of 5-phenyl-1,3,4-oxadiazole and piperazines were rationally designed, synthesized, and pharmacologically evaluated against hAChE, hBChE, and hBACE-1 enzymes for the management of AD. Among the series, compound 5AD comprising pyridyl substitution at terminal nitrogen of piperazine contemplated as a paramount lead compound (hAChE, IC₅₀ = 0.103 ± 0.0172 μM, hBChE, IC₅₀ ≥ 10 μM, and hBACE-1, IC₅₀ = 1.342 ± 0.078 μM). Compound 5AD showed mixed-type enzyme inhibition in enzyme kinetic studies against the hAChE enzyme. In addition, compound 5AD revealed a significant displacement of propidium iodide from the peripheral anionic site (PAS) of hAChE and excellent blood–brain barrier (BBB) permeability in a parallel artificial membrane permeation assay (PAMPA). Besides, 5AD also exhibited anti-Aβ aggregation activity in self- and AChE-induced thioflavin T assay. Further, compound 5AD has shown significant improvement in learning and memory (p < 0.001) against the in vivo scopolamine-induced cognitive dysfunction mice model. The ex vivo study implied that after treatment with compound 5AD, there was a decrease in AChE and malonaldehyde (MDA) levels with an increase in catalase (CAT, oxidative biomarkers) in the hippocampal brain homogenate. Hence, compound 5AD could be regarded as a lead compound and further be explored in the treatment of AD.

An efficient and promising method of treating complex neurodegenerative diseases like Alzheimer's disease (AD) is the multitarget-directed approach. Here in this work, a series of quinazoline derivatives (AV-1 to AV-21) were rationally designed, synthesized, and biologically evaluated as multitargeted directed ligands against human cholinesterase (hChE) and human β-secretase (hBACE-1) that exhibit moderate to good inhibitory effects. Compounds AV-1, AV-2, and AV-3 from the series demonstrated balanced and significant inhibition against these targets. These compounds also displayed excellent blood-brain barrier permeability via the PAMPA-BBB assay. Compound AV-2 significantly displaced propidium iodide (PI) from the acetylcholinesterase-peripheral anionic site (AChE-PAS) and was found to be non-neurotoxic at the maximum tested concentration (80 μM) against differentiated SH-SY5Y cell lines. Compound AV-2 also prevented AChE- and self-induced Aβ aggregation in the thioflavin T assay. Additionally, compound AV-2 significantly ameliorated scopolamine and Aβ-induced cognitive impairments in the in vivo behavioral Y-maze and Morris water maze studies, respectively. The ex vivo and biochemical analysis further revealed good hippocampal AChE inhibition and the antioxidant potential of the compound AV-2. Western blot and immunohistochemical (IHC) analysis of hippocampal brain revealed reduced Aβ, BACE-1, APP/Aβ, and Tau molecular protein expressions levels. The pharmacokinetic analysis of compound AV-2 demonstrated significant oral absorption with good bioavailability. The in silico molecular modeling studies of lead compound AV-2 moreover demonstrated a reasonable binding profile with AChE and BACE-1 enzymes and stable ligand-protein complexes throughout the 100 ns run. Compound AV-2 can be regarded as the lead candidate and could be explored more for AD therapy.

Our present work demonstrates the successful design and synthesis of a new class of compounds based upon a multitargeted directed ligand design approach to discover new agents for use in Alzheimer's disease (AD). All the compounds were tested for their in vitro inhibitory potential against human acetylcholinesterase (hAChE), human butylcholinesterase (hBChE), β-secretase-1 (hBACE-1), and amyloid β (Aβ) aggregation. Compounds 5d and 5f have shown hAChE and hBACE-1 inhibition comparable to donepezil, while hBChE inhibition was comparable to rivastigmine. Compounds 5d and 5f also demonstrated a significant reduction in the formation of Aβ aggregates through the thioflavin T assay and confocal, atomic force, and scanning electron microscopy studies and significantly displaced the total propidium iodide, that is, 54 and 51% at 50 μM concentrations, respectively. Compounds 5d and 5f were devoid of neurotoxic liabilities against RA/BDNF (RA = retinoic acid; BDNF = brain-derived neurotrophic factor)-differentiated SH-SY5Y neuroblastoma cell lines at 10-80 μM concentrations. In both the scopolamine- and Aβ-induced mouse models for AD, compounds 5d and 5f demonstrated significant restoration of learning and memory behaviors. A series of ex vivo studies of hippocampal and cortex brain homogenates showed that 5d and 5f elicit decreases in AChE, malondialdehyde, and nitric oxide levels, an increase in glutathione level, and reduced levels of pro-inflammatory cytokines, tumor necrosis factor alpha (TNF-α) and interleukin-6 (IL-6) mRNA. The histopathological examination of mice revealed normal neuronal appearance in the hippocampal and cortex regions of the brain. Western blot analysis of the same tissue indicated a reduction in Aβ, amyloid precursor protein (APP)/Aβ, BACE-1, and tau protein levels, which were non-significant compared to the sham group. The immunohistochemical analysis also showed significantly lower expression of BACE-1 and Aβ levels, which was comparable to donepezil-treated group. Compounds 5d and 5f represent new lead candidates for developing AD therapeutics.