Neurodegenerative diseases are chronic disorders that affect millions of people (e.g. 6 millions by 2021) in the world in which there is no effective treatment has been implied so far. Alzheimer’s disease (AD) and related dementias are highly prevalent neurodegenerative diseases in the geriatric population, causing long term socioeconomical burden. AD physiopathology involves misfolded proteins' intracellular and post-synaptic accumulation, which deteriorates neuron functions, such as neurotransmission. In AD, misfolding of amyloid-beta fragments 1-40 and 1-42 are responsible for the build-up of amyloid plaques, while the hyperphosphorylated tau (p-tau) protein is involved in forming neurofibrillary tangles. In contrast to neurofibrillary tangles, the spatiotemporal distribution of amyloid plaques does not correlate with progressive cognitive impairment in AD. Therefore, the inhibition of tau and p-tau aggregation can be an effective way of treatment. Our research group continue studying various class of molecules with different chemical functionalities on <i>in vitro</i> inhibition of protein aggregation as initial step of lead discovery process. With our investigations, we have observed that fluor-substituted amide classes of small molecules have comparatively superior and proven activity towards the inhibition of oligomerization and fibrillization, which can be potential for the development of novel drug candidates. Therefore, we move forward and optimize the identified lead amide scaffold by Bioisosteric substitutions or addition. The activity of the proposed analogues was evaluated with thioflavin T fluorescence assays, photo-induced cross-linking of unmodified proteins, and survival assays with human neuroblastoma cells. Further, advantages of small molecular candidates are higher water solubility, cellular infiltration, and easiness to pass the blood brain barrier and straightforward synthesis. In conclusion, the discovery optimization of small molecular candidates exerting an effect on tau and p-tau may lead to improve the future disease-modifying treatments for these devastating neurodegenerative disorders.

Lead modification and structure-activity relationships of halo-substituted amides on inhibition of tau and p-tau aggregation

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