Scientists from the Ural Federal University, the Institute of Organic Synthesis of the Ural Branch of the Russian Academy of Sciences, together with colleagues from India have developed a method for creating safe and non-toxic substances that could become the basis for drugs for Alzheimer's disease. Using the new technology, they synthesized and tested several compounds of tacrine analogues, which toxicity is estimated to be from two to five times lower than that of the known drug. The description of the new method and the compounds obtained was published in the Journal of Heterocyclic Chemistry.
"We believe that our technology will help to create safe substances that will become the basis for future drugs for Alzheimer's disease. Our studies have shown that the toxicity of the resulting substances is two to five times lower than that of tacrine. At the same time, they are effective as they help to increase the level of acetylcholine in the cerebral cortex, which slows down the destruction of neuronal connections. This allows patients to maintain their cognitive functions and lead an active and fulfilling life for as long as possible," explains Nibin Joy Muthipeedika, Senior Researcher at the UrFU Organic Synthesis Laboratory.
The development of Alzheimer's disease occurs because the enzyme acetylcholinesterase (AChE) destroys the neurotransmitter acetylcholine, which plays an important role in the transmission of nerve impulses in the cerebral cortex. Tacrine is an inhibitor, or suppressor, of AChE, which has a positive effect on increasing acetylcholine. However, tacrine is highly toxic and causes serious side effects that lead to disruption of normal liver function. Therefore, the use of tacrine in Alzheimer's disease is not recommended.
"Tacrine was the first substance introduced in 1993 for the treatment of Alzheimer's disease. However, its poor selectivity led to a serious side effect if the form of hepatotoxicity which led to its ban on usage by the US Food and Drug Administration in 2013. At the same time, the drug has shown its efficacy. Therefore, we are working to develop analogues that will have minimal toxicity and similar or greater efficacy in the treatment of Alzheimer's disease," adds Nibin Joy Muthipeedika.
To synthesize new compounds, the scientists used a simple, effective and safe technique: they performed carbonylation reactions with solid compounds that emit carbon monoxide (CO) only when needed.
"Our method can be applied at both laboratory and industrial scale because we do not use toxic carbon monoxide per se and our method does not require high pressure or high temperature equipment," concludes Nibin Joy Muthipeedika.
Reference: Alzheimer's disease is a progressive neurodegenerative disorder that causes gradual loss of cognitive function and memory. The disease was first described in 1906 by German psychiatrist Alois Alzheimer. According to Alzheimer's Disease International (ADI), there are currently more than 55 million people living with Alzheimer's disease worldwide, but this number could rise to 139 million by 2050 as the population ages.
Alzheimer's disease places a heavy financial burden on the global economy. According to ADI, more than $1.3 trillion will be spent on medical care for people with Alzheimer's disease worldwide in 2022. At the same time, the ADI reports that the U.S. will spend $345 billion on the treatment and medical care of people with dementia. By 2050, the U.S. is projected to have spent more than $1.1 trillion annually on Alzheimer's care.
Funding: The study was financially supported by the Russian Science Foundation (Grant No. 21-13-00304) and the Russian Presidential Grant Council (No. NSh-2700.2020.3).
Published in journal: Heterocyclic Chemistry
Source/Credit: Ural Federal University | Anna Marinovich, Sergey Lukyanchenko
Reference Number: phar110823_01
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