Scientists Develop New Molecules as Promising Dual Anti-Cholinesterase Drugs for Alzheimer's Treatment

The research team’s innovative approach resulted in a series of novel molecules that show high effectiveness as dual cholinesterase inhibitors without toxicity, potentially addressing a significant gap in current AD treatment options.

In a major step forward for Alzheimer’s Disease (AD) research, scientists have synthesized new molecules with the potential to treat AD through a combination of synthetic chemistry, computational modeling, and in-vitro testing. This work was conducted by Dr. Prasad Kulkarni and Dr. Vinod Ugale at the Agharkar Research Institute in Pune, India, and supported by the Department of Science and Technology (DST). The research team’s innovative approach resulted in a series of novel molecules that show high effectiveness as dual cholinesterase inhibitors without toxicity, potentially addressing a significant gap in current AD treatment options.

Alzheimer’s disease is the leading cause of dementia, impacting around 75% of all dementia patients and primarily affecting those over the age of 65. The disease disrupts brain function by impairing neuron communication, leading to severe cognitive decline. Current treatments include one N-methyl-D-aspartate (NMDA) receptor antagonist (Memantine) and three anti-cholinesterase drugs (Donepezil, Rivastigmine, and Galantamine), though these often provide only short-term benefits and can cause serious side effects, limiting their clinical use.

To tackle these challenges, the researchers employed a one-pot, three-component reaction method to synthesize a series of molecules with high yields. These molecules were rigorously tested for their ability to inhibit cholinesterase enzymes and were confirmed to be non-toxic through in-vitro assays. Notably, one lead molecule showed high selectivity for acetylcholinesterase over butyrylcholinesterase, which is beneficial in reducing adverse side effects associated with non-selective cholinesterase inhibition.

Molecular dynamics simulations further validated the stability of these molecules in the enzyme’s active site, with stable interactions observed between the molecules and key amino acids, reinforcing their efficacy and specificity. This structural stability within the enzyme pocket enhances their potential as durable and efficient anti-AD agents.

“These molecules mark a significant advance, holding promise for dual anti-cholinesterase drug development, which could be used in conjunction with other treatments to improve outcomes for AD patients,” said Dr. Kulkarni. Moving forward, the team plans to develop and test novel carbazole and chromene analogues with additional anti-AD properties, potentially broadening the therapeutic benefits.

The breakthrough of creating selective, non-toxic cholinesterase inhibitors through a multi-faceted scientific approach could revolutionize treatment options for AD, providing a much-needed option to slow disease progression and improve patient quality of life.