New Thieno[3,2-d]pyrimidin-4(3H)-one Schiff Bases as Selective Antileishmanial Agents

The present study aimed to design, synthesize, and evaluate a new series of thieno[3,2-d]pyrimidin-4(3H)-one-based Schiff bases as potential antileishmanial agents against Leishmania major (L. major). A series of twenty thieno[3,2-d]pyrimidine Schiff base derivatives were synthesized and characterized using FTIR, NMR, and HRMS techniques. Their antipromastigote activities were evaluated in vitro against L. major, while cytotoxic effects were assessed on HUVECs to determine selectivity indices. The most active compound was further investigated using molecular docking against several L. major proteins. Among the tested compounds, compound 12, bearing a 2-hydroxy-5-bromophenyl moiety, exhibited the most potent activity against L. major promastigotes with an IC50 value of 13.7 µM, along with a favorable selectivity index (SI = 17.5), outperforming the reference drug miltefosine (IC50 = 31 µM and SI = 0.2). Docking studies demonstrated that compound 12 showed the strongest binding affinity toward phosphodiesterase B1, supported by a docking score of −9.042 kcal/mol and an MM-GBSA value of −67.21 kcal/mol. This study highlights thieno[3,2-d]pyrimidin-4(3H)-one as a promising scaffold in the context of in vitro antileishmanial screening and suggests the role of ortho-phenolic substitution in enhancing activity and selectivity. Compound 12 emerges as a promising lead, warranting further optimization and biological evaluation in future studies.