Presentation_1_Structure-Based Design, Synthesis, Biological Evaluation, and Molecular Docking of Novel PDE10 Inhibitors With Antioxidant Activities.PDF

<p>Phosphodiesterase 10 is a promising target for the treatment of a series of central nervous system (CNS) diseases. Imbalance between oxidative stress and antioxidant defense systems as a universal condition in neurodegenerative disorders is widely studied as a potential therapy for CNS diseases, such as Alzheimer's disease (AD), Parkinson's disease (PD) and amyotrophic lateral sclerosis (ALS). To discover multifunctional pharmaceuticals as a treatment for neurodegenerative diseases, a series of quinazoline-based derivatives with PDE10 inhibitory activities and antioxidant activities were designed and synthesized. Nine out of 13 designed compounds showed good PDE10 inhibition at the concentration of 1.0 μM. Among these compounds, eight exhibited moderate to excellent antioxidant activity with ORAC (oxygen radical absorbance capacity) value above 1.0. Molecular docking was performed for better understanding of the binding patterns of these compounds with PDE10. Compound 11e, which showed remarkable inhibitory activity against PDE10 and antioxidant activity may serve as a lead for the further modification.</p

Prostaglandin Derivatives: Nonaromatic Phosphodiesterase‑4 Inhibitors from the Soft Coral <i>Sarcophyton ehrenbergi</i>

Ten new prostaglandin derivatives (PGs), sarcoehrendins A–J (<b>1</b>–<b>10</b>), together with five known analogues (<b>11</b>–<b>15</b>) were isolated from the soft coral <i>Sarcophyton ehrenbergi</i>. Compounds <b>4</b>–<b>8</b> represented the first examples of PGs featuring an 18-ketone group. The structures including the absolute configurations were elucidated on the basis of spectroscopic analysis and chemical evidence. All of the isolates and six synthetic analogues (<b>3a</b>, <b>3b</b>, <b>4a</b>, and <b>11a</b>–<b>11c</b>) were screened for inhibitory activity against phosphodiesterase-4 (PDE4), which is a drug target for the treatment of asthma and chronic obstructive pulmonary disease. Compounds <b>2</b>, <b>10</b>, <b>11a</b>, <b>11b</b>, and <b>13</b>–<b>15</b> exhibited inhibition with IC₅₀ values less than 10 μM, and compound <b>15</b> (IC₅₀ = 1.4 μM) showed comparable activity to the positive control rolipram (IC₅₀ = 0.60 μM). The active natural PGs (<b>2</b>, <b>10</b>, and <b>13</b>–<b>15</b>) represent the first examples of PDE4 inhibitors without an aromatic moiety, and a preliminary structure–activity relationship is also proposed