Malaria is an infectious disease caused by Plasmodium spp. parasites, with widespread drug resistance to most antimalarial drugs. We report the development of two 3D-QSAR models based on comparative molecular field analysis (CoMFA), comparative molecular similarity index analysis (CoMSIA), and a 2D-QSAR model, using a database of 349 compounds with activity against the P. falciparum 3D7 strain. The models were validated internally and externally, complying with all metrics (q² > 0.5, r²_test > 0.6, r²_m > 0.5, etc.). The final models have shown the following statistical values: r²_test CoMFA = 0.878, r²_test CoMSIA = 0.876, and r²_test 2D-QSAR = 0.845. The models were experimentally tested through the synthesis and biological evaluation of ten quinoline derivatives against P. falciparum 3D7. The CoMSIA and 2D-QSAR models outperformed CoMFA in terms of better predictive capacity (MAE = 0.7006, 0.4849, and 1.2803, respectively). The physicochemical and pharmacokinetic properties of three selected quinoline derivatives were similar to chloroquine. Finally, the compounds showed low cytotoxicity (IC₅₀ > 100 µM) on human HepG2 cells. These results suggest that the QSAR models accurately predict the toxicological profile, correlating well with experimental in vivo data.

Background: Leishmania amazonensis, one of the causative agents of cutaneous leishmaniasis, is responsible for a neglected tropical disease affecting nearly one million individuals worldwide. Although clinical treatments are available, their effectiveness is often compromised by high toxicity and limited selectivity. Methods: From a database, 64 chalcone derivatives were studied using Comparative Molecular Similarity Indices Analysis (CoMSIA) and Hansch analysis (2D-QSAR) to construct predictive computational models. Internal and external validation criteria were applied to identify structural determinants associated with antileishmanial activity. Based on these insights, twelve novel quinoline–chalcone hybrids were designed, synthesized, and biologically evaluated against L. amazonensis. Results: The most robust CoMSIA model combined steric and hydrogen-bond acceptor fields (CoMSIA-SA), while Hansch analysis highlighted electronic descriptors—specifically LUMO energy and the global electrophilicity index—as critical for parasite growth inhibition. Guided by these computational findings, a new series of 12 hybrid quinoline–chalcone derivatives (E001–E012) was synthesized through a two-step procedure, achieving overall yields of 43–71%. Biological assays demonstrated that four compounds displayed inhibitory activity comparable to amphotericin B. Furthermore, physicochemical profiling and in silico pharmacokinetic predictions for the most active compounds (E003, E005, E006, and E011) indicated favorable biocompatibility and drug-like properties. Conclusions: These results underscore the value of an integrative computational–experimental approach in the rational design of next-generation L. amazonensis inhibitors, reinforcing chalcone-based scaffolds as promising pharmacophoric frameworks for antileishmanial drug discovery.

The Gould–Jacobs reaction for the synthesis of ethyl 4-quinolone-3-carboxylate derivatives is described. Thus, the condensation of 4-subtituted anilines and EMME to give the corresponding diethyl anilinomethylene malonate was carried out via neat MW irradiation or refluxing ethanol. These intermediates underwent Eaton’s reagent-catalyzed cyclisation with good to excellent yields. For the first step, the MW reaction took only 7 min compared with the two hours required for conventional heating, yet the yields were comparable in almost all cases. A series of eight 4-quinolone derivatives was obtained with good yields under mild conditions and with short reaction times.

The naturally occurring alkaloid tryptanthrin is a valuable scaffold in medicinal chemistry with anti-inflammatory, antibacterial, antiparasitic, and anticancer properties. However, its conventional synthesis requires harsh conditions and harmful solvents like toluene, whereas previous microwave methods yielded only 30%. To address this, we present an efficient and eco-friendly microwave-assisted synthesis. Using isatin and isatoic anhydride as starting materials, this completely solvent-free methodology reduces reaction time to just 7 min, suppresses by-product formation, and achieves a superior yield. Additionally, we provide the complete assignment of its ¹H and ¹³C-NMR spectra. This advance offers a clean and sustainable route for pharmaceutical development.