Mitigating SARS-CoV-2–exacerbated neuroinflammation and Alzheimer's pathology: Synthesis of quinoline-based dual inhibitors targeting cysteine and aspartyl proteases

Viral and neurodegenerative proteases, such as the cysteine protease and aspartyl protease, offer strategic targets in a multitarget therapeutic approach for Alzheimer's disease, especially when viral infection may exacerbate neurological degeneration. To establish a multitarget therapeutic for treating Alzheimer's disease, we chose β-secretase (BACE-1), an aspartyl protease, and the SARS-CoV-2 main protease (Mpro), a cysteine protease, as dual targets. In search of BACE-1 and M^pro inhibitors, a set of novel quinoline-4-carboxamide derivatives (2a-k, 3a-c, 4a-d, 5a-c, 6a-c) was synthesized using the Suzuki coupling reaction in good to excellent yields. All the synthesized compounds were screened in vitro for their potential inhibitory activities against two proteases. Compounds 2e, 6b, and 6c emerged as dual inhibitors of both proteases. Furthermore, a kinetic study revealed the mechanism of BACE-1 inhibition by compound 6c. Safety profiling of the most potent dual inhibitor 6c was performed via an in vivo acute cytotoxicity assay on Swiss albino mice. Molecular docking studies were conducted against aspartyl protease (2HM1) and cysteine protease (6XHM) to elucidate the binding interaction of synthesized quinoline derivatives. The compound 6c exhibited strong binding affinities through multiple hydrogen bonds, π-Sulfur and π-π stacking interactions, within key subpockets of both targets, supporting inhibitory potential. These studies revealed that the lead compound 6c could be a good drug candidate with further structural modifications.