A library of 69 synthetic benzenesulfonyl derivatives of heterocycles, with drug-like properties, was assayed for in vitro antiparasitic activity and the results were added to our previous reports for a comprehensive SAR discussion. Seven compounds showed an IC₅₀ between 0.25-3μM against L. donovani and low cytotoxicity. Compound 1-(2,3,5,6-tetramethylphenylsulfonyl)-2-methylindoline (G16), was particularly interesting with an IC₅₀ similar to the reference drug miltefosine. In addition, seven compounds showed an IC₅₀ below 6µM against T. cruzi, and three of them (E3, E9 and G3) were identified as lead scaffolds for further optimization based on their activity-toxicity profile. Furthermore, two promising structures (B15 and G15) have shown moderate inhibitory activity against P. falciparum. In general, the presence of a benzenesulfonyl moiety improves the antiparasitic activity of the heterocycles included in this study (with exception of T. b. rhodesiense) validating the criteria used in the selection of the fragment-based drug design approach. Finally, from the SAR analysis it could be concluded that the presence of electron withdrawing and lipophilic groups were favorable for the antiparasitic activity.