A novel series of phenithionate analogues or derivatives were designed and synthesized using phenithionate as the lead compound, and their bioactivities were studied. Their structures were confirmed by <sup>1</sup>H NMR, <sup>13</sup>C NMR, HR-ESI-MS, and elemental analysis, respectively. The results of <i>in vitro</i> inhibitory activity measurement proved that compounds <b>5a</b>, <b>5c</b>, <b>5g</b>, <b>5i</b>, <b>5m</b> and <b>5o</b> had a better inhibitory effect on larva and imago schistosoma. Among them, the inhibitory activity of compound <b>5i</b> for larva schistosoma was IC<sub>50</sub> = 5.21 ± 0.04 μg mL<sup>-1</sup>, and for imago schistosoma it was IC<sub>50</sub> = 6.35 ± 0.08 μg mL<sup>-1</sup>. Moreover, the experimental results of <i>in vivo</i> anti-schistosomiasis activity measurement showed that they had good anti-schistosomiasis activity. Therefore, these compounds had better drugability.