Nampally Sreenivasachary

Gelation-driven component selection in the generation of constitutional dynamic hydrogels based on guanine-quartet formation

The guanosine hydrazide 1 yields a stable supramolecular hydrogel based on the formation of a guanine quartet (G-quartet) in presence of metal cations. The effect of various parameters (concentration, nature of metal ion, and temperature) on the properties of this gel has been studied. Proton NMR spectroscopy is shown to allow a molecular characterization of the gelation process. Hydrazide 1 and its assemblies can be reversibly decorated by acylhydrazone formation with various aldehydes, resulting in formation of highly viscous dynamic hydrogels. When a mixture of aldehydes is used, the dynamic system selects the aldehyde that leads to the most stable gel. Mixing hydrazides 1, 9 and aldehydes 6, 8 in 1:1:1:1 ratio generated a constitutional dynamic library containing the four acylhydrazone derivatives A, B, C, and D. The library constitution displayed preferential formation of the acylhydrazone B that yields the strongest gel. Thus, gelation redirects the acylhydrazone distribution in the dynamic library as guanosine hydrazide 1 scavenges preferentially aldehyde 8, under the pressure of gelation because of the collective interactions in the assemblies of G-quartets B, despite the strong preference of the competing hydrazide 9 for 8. Gel formation and component selection are thermoreversible. The process amounts to gelation-driven self-organization with component selection and amplification in constitutional dynamic hydrogels based on G-quartet formation and reversible covalent connections. The observed self-organization and component selection occur by means of a multilevel self-assembly involving three dynamic processes, two of supramolecular and one of reversible covalent nature. They extend constitutional dynamic chemistry to phase-organization and phase-transition events.

Discovery and structure activity relationship of small molecule inhibitors of toxic β-amyloid-42 fibril formation

Background: Self-aggregation of β-amyloid plays an important role in the pathogenesis of Alzheimer disease. Results: Small molecule inhibitors of β-amyloid fibril formation reduce β-amyloid mediated cell toxicity. Conclusion: Rational design led to the successful development of small molecule inhibitors of β-amyloid oligomerization and toxicity. Significance: Small molecules targeting β-amyloid misfolding may provide new treatments for Alzheimer disease. Increasing evidence implicates Aβ peptides self-assembly and fibril formation as crucial events in the pathogenesis of Alzheimer disease. Thus, inhibiting Aβ aggregation, among others, has emerged as a potential therapeutic intervention for this disorder. Herein, we employed 3-aminopyrazole as a key fragment in our design of non-dye compounds capable of interacting with Aβ42 via a donor-acceptor-donor hydrogen bond pattern complementary to that of the β-sheet conformation of Aβ42. The initial design of the compounds was based on connecting two 3-aminopyrazole moieties via a linker to identify suitable scaffold molecules. Additional aryl substitutions on the two 3-aminopyrazole moieties were also explored to enhance π-π stacking/hydrophobic interactions with amino acids of Aβ42. The efficacy of these compounds on inhibiting Aβ fibril formation and toxicity in vitro was assessed using a combination of biophysical techniques and viability assays. Using structure activity relationship data from the in vitro assays, we identified compounds capable of preventing pathological self-assembly of Aβ42 leading to decreased cell toxicity.

Discovery and characterization of novel indole and 7-azaindole derivatives as inhibitors of β-amyloid-42 aggregation for the treatment of Alzheimer’s disease

The aggregation of amyloid-β peptides into cytotoxic oligomeric and fibrillary aggregates is believed to be one of the major pathological events in Alzheimer disease. Here we report the design and synthesis of a novel series of indole and 7-azaindole derivatives containing, nitrile, piperidine and N-methyl-piperidine substituents at the 3-position to prevent the pathological self-assembly of amyloid-β. We have further demonstrated that substitution of the azaindole and indole derivatives at the 3 positions is required to obtain compounds with improved physicochemical properties to allow brain penetration.

Synthesis and structure-activity relationship of 2,6-disubstituted pyridine derivatives as inhibitors of β-amyloid-42 aggregation.

It is assumed that amyloid-β aggregation is a crucial event in the pathogenesis of Alzheimers disease. Novel 2,6-disubstituted pyridine derivatives were designed to interact with the β-sheet conformation of Aβ via donor-acceptor-donor hydrogen bond formation. A series of pyridine derivatives were synthesized and tested regarding their potential to inhibit the aggregation of Aβ. The 2,6-diaminopyridine moiety was identified as a key component to inhibit Aβ aggregation. Overall, compounds having three 2,6-disubstituted pyridine units separated by at least one C2- or C3-linker displayed the most potent inhibition of Aβ aggregation.

Visualization of beta-amyloid plaque reduction by small-molecule beta-amyloid oligomer aggregation inhibitors in hAPPSL transgenic mice

Background: Alzheimer’s disease (AD) is the most common age-related neurodegenerative disorder affecting an estimated 35 million patients. Current treatment options are limited to drugs treating the symptoms and do not slow or reverse disease progression. Thus, a disease modifying drug would be a major therapeutic breakthrough towards treatment of the disease. The formation of A b fibrils and their deposition into neurotoxic amyloid plaques is considered an initial event in the progression of AD. A central therapeutic aim in AD is the removal of toxic amyloid-b deposit, which can be achieved by inhibition of Ab aggregation. Previously, we have identified a compound capable of reducing Ab plaques and improvingmemory capacity in tg-mice. Herein, we report the effect of this compound on longitudinal Ab plaque dynamics in tg-mice.Methods: Female hAPP SL tg-mice (9-12 months) were operated for implantation of a cranial window and tg-mice still having a transparent cranial window 4 weeks after implantation were used for the study. The combination of an intravenously administered imaging agent and in vivo two-photon microscopy allowed the visualization of densecore A b plaques on Day 0. The values obtained on Day 0 served as baseline in the subsequent 15 day long longitudinal study performed on the same animal treated orally once a day with either vehicle or compound. Results: The vehicle-treated tg-mice exhibited no clear trend to either growth or decrease in plaque size as the diameter of plaques on Day 15 did not differ statistically significant from Day 0, but the plaque density increased by 17 %. In contrast, compound treated tg-mice showed a strong, statistically significant decrease in the size of all pre-existing plaques as the plaque volume decreased by 75 % leading to a decrease in Ab plaque load. Conclusions: We have discovered a small molecule with suitable pharmacokinetic properties which prevented/reversed the pathological toxic effect of Ab aggregation leading to a statistically significant decrease in plaque size in an animal model of AD. Thus, this compound could be a promising candidate for the treatment of AD.