Chemical Evolution and Biological Evaluation of Natural Products for Efficient Therapy of Acute Lung Injury

Acute lung injury (ALI) is one of the most common complications in COVID-19 and also a syndrome of acute respiratory failure with high mortality rates, but lacks effective therapeutic drugs. Natural products provide inspiration and have proven to be the most valuable source for bioactive molecule discovery. In this study, the chemical evolution of the natural product Tanshinone IIA (Tan-IIA) to achieve a piperidine-fused scaffold through a synthetic route of pre-activation, multi-component reaction, and post-modification is presented. Through biological evaluation, it is pinpointed that compound 8b is a standout candidate with remarkable anti-inflammation and anti-oxidative stress properties, coupled with low toxicity. The mechanistic study unveils a multifaceted biological profile of 8b and shows that 8b is highly efficient in vivo for the treatment of ALI. Therefore, this work not only provides an effective strategy for the treatment of ALI, but also offers a distinctive natural product-inspired drug discovery. Acute lung injury (ALI) is an acute respiratory failure with high mortality rates, but lacks effective therapy. Herein, a chemical evolution of natural products for efficient therapy of ALI is reported. A series of Tanshinone IIA-inspired compounds are achieved through a concise synthesis. The biological evaluation identifies compound 8b with a multiple biological profile of anti-inflammation and anti-oxidation as therapeutics.image