MAO-B inhibitor(HEC)

The reintroduction of the pseudorabies virus (PRV) has led to the emergence of epidemics in some pig farms in China, resulting in significant economic losses. Moreover, the number of human infections with PRV has increased. Therefore, research into the prevention and treatment of PRV strains is imperative. In this work, the PRV DNA polymerase (DNA pol) was found to exhibit a high degree of sequence and structural similarity to the herpes simplex virus 1 (HSV-1) DNA pol. Consequently, we provided the first experimental evidence that PNU-183792, a non-nucleoside inhibitor of HSV-1, inhibited PRV replication in cell assay, with an EC₅₀ of 100 pM, providing the basis for further studies on PRV inhibitors. Then, with the great help of reinforcement learning, some new potential hits were discovered based on the HSV-1 DNA pol inhibitors. One of the compounds, c14, which showed significant anti-PRV potency and safety, with an EC₅₀ of 14 pM and a CC₅₀ of 343.7 μM, can be considered as a highly promising lead compound to support drug discovery and development for anti-PRV.

Linezolid, a widely used oxazolidinone antibiotic, exhibits potent activity against resistant bacterial infections but is associated with serotonergic toxicity, primarily due to its inhibition of monoamine oxidase (MAO). MAOs, consisting of MAO-A and MAO-B isoforms, play crucial roles in neurotransmitter metabolism, with implications for neurodegenerative disorders like Parkinson's and Alzheimer's diseases. This study aims to optimize Linezolid's structure to transform it into a selective MAO-B inhibitor. Utilizing structure-activity and structure-toxicity relationship approaches, novel analogues of Linezolid were synthesized by replacing its oxazolidinone ring with a thiadiazole scaffold. Among the synthesized compounds, 6b emerged as a lead candidate, displaying a remarkable MAO-B inhibitory activity (IC₅₀ = 0.03 μM) and 464-fold selectivity over MAO-A, compared to the standard drugs Pargyline (IC₅₀ = 0.14 μM) and Clorgyline (IC₅₀ = 1.85 μM). Furthermore, docking and molecular dynamics simulations corroborated the high affinity and stability of compound 6b in the MAO-B enzyme's binding pocket. These findings suggest that optimized Linezolid analogues, particularly compound 6b, hold promise as selective MAO-B inhibitors, offering therapeutic potential for treating neurodegenerative diseases while avoiding the risks associated with serotonergic toxicity.