Scientists have designed and synthesized novel molecules through a blend of synthetic, computational, and in-vitro studies for treating Alzheimer's Disease (AD). These non-toxic molecules could be effective in the treatment of the disease.

Neurons are specialized cells in the brain that form the nervous system. The nervous system communicates between the brain and the rest of the body. Alzheimer's disease (AD) disrupts this communication, causing limitations in learning and memory and changes in adaptive behaviour. AD occurs due to an imbalance in certain hormones.

AD is the most common form of dementia and constitutes around 75% of all dementia cases. Of the about 55 million people worldwide with dementia, 60% to 70% are estimated to have AD. The disease most commonly affects people over the age of 65. The causes mainly include a combination of age-related brain changes and genetic, environmental, and lifestyle factors. The treatment may be able to slow dementia and improve quality of life, but these conditions are progressive, and symptoms of the disease worsen over time.

To date, treatment options available to cure AD are limited to one N-methyl-D-aspartate receptor antagonist (Memantine) and three anti-cholinesterase drugs (Donepezil, Rivastigmine, Galantamine). However, approved anti-cholinesterase drugs suffer from limitations of short-term benefits and serious side effects that restrict their clinical applications.

Recently, Dr. Prasad Kulkarni and Dr. Vinod Ugale (SERB TARE Fellow), scientists from Agharkar Research Institute, Pune, an autonomous institute of Department of Science and Technology, have developed a rapid one-pot, three-component reaction with high synthetic yields to generate novel molecules. In-vitro screening methods were then used to assess the potency and cytotoxicity of these molecules. Developed molecules were found to be non-toxic and effective against cholinesterase enzymes. The lead molecule was found to be selective for acetylcholinesterase with a significant selectivity ratio compared to butyrylcholinesterase. Effective molecules have also shown good stability in the pocket of enzymes through interactions with amino acids during molecular dynamics simulation.

Finally, molecules identified through a blend of synthetic, computational, and in-vitro studies have proved to be good dual cholinesterase inhibitors. They could be further optimized to develop more effective anti-AD ligands. Utilized multipronged approaches with modern scientific validation offer the potential for holistic health and wellness of society. Together, these molecules could be exploited to develop dual anti-cholinesterase drugs to treat AD in combination with other drugs. In future studies, we will plan to synthesize novel substituted carbazole and chromene clubbed analogs with additional anti-AD properties.

The discovery is published in the journal Molecular Diversity (https://doi.org/10.1007/s11030-024-10859-z). The work was sponsored under the SERB TARE scheme.

Fig. 1. Development of novel 9H-carbazole-4H-chromene hybrids 4 (a-l) as potential anti-Alzheimer's agents.