Mavacamten Derivatives Significantly Ameliorate Lipopolysaccharide-Induced Acute Lung Injury, Partly by Modulating Nuclear Factor Kappa-B Signaling

Acute lung injury (ALI) and Acute respiratory distress syndrome (ARDS) are critical pulmonary disorders marked by excessive inflammation and cytokine storm, often resulting in respiratory failure and high mortality, especially if untreated. Mavacamten, a first-in-class cardiac myosin ATPase inhibitor (small-molecule), is known for reducing pathological hypercontractility; however, its role in ALI/ARDS remains unexplored. Recently, we synthesized and reported the novel mavacamten derivatives incorporating the 6-chloro-3-isopropyl-1-methylpyrimidine-2,4-(1<i>H</i>,3<i>H</i>)-dione scaffold via a catalyst-free method. This study aimed to investigate the anti-inflammatory and antioxidant activities of mavacamten and its derivatives (17 compounds) using LPS-induced inflammation models in vitro and in vivo (LPS-induced mouse model). Initial screening by IL-6 inhibition results demonstrated that mavacamten and its derivatives (<b>5d</b> and <b>5o</b>) significantly reduced IL-6 levels compared to the LPS control and other derivatives. Further, in vitro analysis showed <b>5d</b> and <b>5o</b> treatment significantly downregulated the LPS-induced elevation of several key pro-inflammatory markers (IL-1β, IL-6, TNF-α, CCL2, and F4/80) and oxidative stress indicators (ROS, nitric oxide, and <i>p</i>-cofilin), while restoring caveolin-1 levels. Furthermore, in vivo administration of <b>5d</b> and <b>5o</b> (1.5 and 3 mg/kg) significantly attenuated LPS-induced increase in lung and heart indices, reduced systemic inflammatory markers (monocytes, WBCs, and neutrophils), and restored platelet and lymphocyte counts, indicating mitigation of inflammatory cell infiltration at the injury site. Gene and protein expression analyses confirmed a reduction in the expression of inflammatory markers dose dependently. Histopathological examination revealed that <b>5d</b> and <b>5o</b> markedly alleviated LPS-induced lung (alveolar edema, wall thickening) and heart (myocardial inflammation) abnormalities. Mechanistic findings demonstrate that compounds <b>5d</b> and <b>5o</b> effectively reduced the LPS-induced inflammation and tissue injury by modulating NF-κB signaling in both in vitro and in vivo conditions, highlighting their translational potential as therapeutic candidates for the treatment of ALI/ARDS.