Efficient Synthesis of Tacrine Analogues Using 2-Aminothiophene-3-Carbonitril as a Key Precursor

Alzheimer's disease is a complex and progressive neurodegenerative disorder characterized by severe cognitive decline, which is notably linked to a deficiency in acetylcholine, an essential neurotransmitter for memory. Addressing this major public health challenge, the development of cholinesterase inhibitors remains a key therapeutic strategy. Aromatic heterocycles constitute an essential class in organic chemistry due to their structural diversity and multiple applications. Among them, sulfur heterocycles (S-heterocycles), and particularly the thiophene ring, stand out as privileged structures in medicinal chemistry thanks to the bioisosteric equivalence of this nucleus with the phenyl group

In this work, 2-aminothiophene-3-carbonitrile was exploited as a key building block for the design of novel hybrid analogues of Tacrine, a scaffold of historical interest in the treatment of this pathology. Consequently, a series of derivatives was successfully synthesized via the Friedländer reaction. This synthetic work, actively carried out by our research team in our laboratory, was achieved through an efficient one-pot sequential cyclocondensation with various cyclic ketones, providing yields ranging from 40 to 60%.

The chemical structures of the target compounds were unambiguously confirmed by infrared (IR) spectroscopy. These specific results highlight the therapeutic potential of these newly developed systems, thereby opening interesting perspectives for further in vitro biological evaluations.