Designed Chalcone-Dihydropyrimidinone hybrid compounds were synthesized expeditiously. The hybridization was performed through the Copper-catalyzed Alkyne-Azide Cycloaddition (CuAAC) from the propargyloxy chalcones and azido-dihydropyrimidinones. The hybrid products were prepared in five steps with a 30–48% overall yield. Most of the compounds showed selective cytotoxicity and lower IC₅₀ values (<10 µM) against MCF-7 (breast adenocarcinoma) cancer. Cytotoxicity was also observed against OVCAR-3 (ovary, adenocarcinoma), NCI/ADR-RES (ovary, multidrug-resistant adenocarcinoma), and U-251 (brain, glioblastoma) cell lines. The potency of the most active hybrids 9d, 9g, and 9h was greater than the individual parental compounds, suggesting the effectiveness of molecular hybridization on the cytotoxicity. Compounds 9d, 9g, and especially 9h showed high selectivity for breast cancer cells (MCF-7) regarding human keratinocytes (HaCaT). Molecular docking calculations for the 9d, 9g, and 9h hybrids in the active site of estrogen supported the hypothesis that the compounds act as ER-α antagonists, disrupting the cell proliferation process of MCF-7, corroborating the potency and selectivity observed for this tumoral cell line.

This study presents the design and synthesis of a series of quinazoline-dihydropyrimidinone hybrid compounds with potential antichagasic and antileishmanial activities, addressed to fight against neglected tropical diseases (NTDs). All compounds were evaluated against the epimastigote and trypomastigote forms of Trypanosoma cruzi and the promastigote forms of Leishmania infantum, Leishmania braziliensis, Leishmania amazonensis, and Leishmania major. Among them, hybrids 7a and 7c showed significant activity against all parasites, surpassing the potency of the reference drugs miltefosine and benznidazole. Molecular docking simulation indicated strong interactions of hybrids 7a and 7c with key parasitic enzymes – such as cruzain from T. cruzi and sterol 14-alpha demethylase from L. infantum; dihydroorotate dehydrogenase from L. braziliensis; nucleoside diphosphate kinase (NDK) from L. amazonensis; and N-myristoyltransferase from L. major - which may underlie their observed in vitro efficacy.