A team of scientists from Agharkar Research Institute (ARI), Pune, has made significant strides in the fight against Alzheimer’s Disease (AD) by designing and synthesizing novel, non-toxic molecules that show potential in treating this debilitating condition. 

Led by Dr. Prasad Kulkarni and Dr. Vinod Ugale, a Science and Engineering Research Board (SERB) TARE Fellow, the team utilized a blend of synthetic, computational, and in-vitro methods to generate these molecules, which have shown promise as dual cholinesterase inhibitors—vital for targeting Alzheimer’s symptoms.

Alzheimer’s, the most common form of dementia, disrupts neuron function, severely affecting learning, memory, and behavior. Constituting around 75% of all dementia cases, AD currently affects approximately 55 million people globally, primarily impacting those over 65. 

While the causes of AD remain complex and involve age-related brain changes, genetics, environmental, and lifestyle factors, the disease’s progression severely impacts quality of life. Existing treatments, which include the N-methyl-D-aspartate receptor antagonist Memantine and anti-cholinesterase drugs such as Donepezil, Rivastigmine, and Galantamine, offer only limited short-term benefits and are often accompanied by significant side effects.

The ARI team addressed these limitations by developing an innovative one-pot, three-component reaction method, achieving high synthetic yields to create novel molecules that target cholinesterase enzymes, essential in regulating brain signaling affected by AD. 

Their in-vitro screening revealed that these molecules are non-toxic and selectively inhibit acetylcholinesterase, a key enzyme implicated in AD, with promising selectivity over butyrylcholinesterase. 

The stability and interaction of these molecules within enzyme pockets, as verified through molecular dynamics simulations, underscore their effectiveness and stability.

“These molecules offer a new pathway to improve the treatment options for AD by potentially minimizing the progression of dementia and enhancing patients’ quality of life,” Dr. Kulkarni said, highlighting the potential societal impact.

The dual-action potential of these molecules as cholinesterase inhibitors opens avenues for the development of combination therapies. 

Future research will focus on synthesizing carbazole and chromene clubbed analogs with additional anti-AD properties, offering hope for more effective therapies that integrate well with modern scientific approaches. With continued optimization, these molecules may provide the basis for innovative treatments, promising new avenues for improving the lives of millions facing Alzheimer’s Disease.