The Janus kinases (JAKs) are a family of intracellular tyrosine kinases that play an essential role in many basic biological processes, such as apoptosis and inflammation. Thus any dysfunction of the proteins in this pathway may lead to a variety of diseases, including cancer and diseases that affect the immune system, such as severe combined immune deficient (SCID). Marine biological resources have become an important source in new drug research and development due to their diversity, complexity and speciality. In this study, Marine alkaloid Neobacillamide A was isolated from the greedy and stubborn sponge symbiotic Bacillus atrophicus C89 in the South China Sea. Totally 24 novel marine alkaloid Neobacillamide A derivatives were designed and synthesized, which were evaluated for their inhibitory activity against JAK/STAT signaling pathway and their cytotoxicity to A549 cells. Compounds 13c, 13o, 14d, 14g and 14h showed potent JAK/STAT inhibition capability (concentration of 25 mu mol L-1, all inhibitory potencies were above 60%), especially compound 14g exhibited superior JAK/STAT inhibition effect (89.70% inhibition). In addition, all these compounds with a concentration of 25 mu mol L-1 displayed weak or no cytotoxicity to A549 cells, which means that these Neobacillamide A derivatives with JAK/STAT inhibition capability may have potential anti-inflammatory function.