2D/3D-QSAR Model Development Based on a Quinoline Pharmacophoric Core for the Inhibition of Plasmodium falciparum : An In Silico Approach with Experimental Validation

• Published in: Pharmaceuticals (Basel, Switzerland) Vol. 17; no. 7; p. 889
• Main Authors: Lorca, Marcos, Muscia, Gisela C, Pérez-Benavente, Susana, Bautista, José M, Acosta, Alison, González, Cesar, Sabadini, Gianfranco, Mella, Jaime, Asís, Silvia E, Mellado, Marco
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 04.07.2024
• Subjects: 2D- and 3D-QSAR models; Antiparasitic agents; biocompatibility; Biological activity; drug design; Drug resistance; experimental validation; Infections; Malaria; quinoline synthesis; Vaccines; Africa; 2D- and 3D-QSAR models; quinoline synthesis; malaria; biocompatibility; drug design; experimental validation
• ISSN: 1424-8247; 1424-8247
• DOI: 10.3390/ph17070889

Malaria is an infectious disease caused by 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 3D7 strain. The models were validated internally and externally, complying with all metrics (q > 0.5, r > 0.6, r > 0.5, etc.). The final models have shown the following statistical values: r CoMFA = 0.878, r CoMSIA = 0.876, and r 2D-QSAR = 0.845. The models were experimentally tested through the synthesis and biological evaluation of ten quinoline derivatives against 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 (IC > 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.