Myeloid differentiation primary response protein 88 (MyD88) is crucial to immune cascades mediated by Toll-like receptors (TLRs) and interleukin-1 receptors (IL-1Rs). MyD88 dysregulation has been linked to a wide variety of inflammatory diseases, making it a promising new target for anti-inflammatory and cancer therapy development. In this study, 46 compounds were designed and synthesized inspired by virtual screen hit. The anti-inflammatory activity of designed compounds was evaluated biologically, and c17 was discovered to have a high binding affinity with MyD88. It inhibited the interaction of TLR4 and MyD88 and suppressed the NF-κB pathway. In addition, c17 treatment led to the accumulation in the lungs of rats and attenuated LPS-induced ALI mice model. Furthermore, c17 showed negligible toxicity in vivo. Together, these findings suggest that c17 may serve as a potential therapeutical method for the treatment of ALI and as a lead structure for the continued development of MyD88 inhibitors.