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

• Main Authors: Marcos Lorca (Author), Gisela C. Muscia (Author), Susana Pérez-Benavente (Author), José M. Bautista (Author), Alison Acosta (Author), Cesar González (Author), Gianfranco Sabadini (Author), Jaime Mella (Author), Silvia E. Asís (Author), Marco Mellado (Author)
• Format: Book
• Published: MDPI AG, 2024-07-01T00:00:00Z.
• Subjects: article
• Online Access: Connect to this object online.

Summary

Malaria is an infectious disease caused by <i>Plasmodium</i> 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 <i>P. falciparum</i> 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 <i>P. falciparum</i> 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.

Item Description

10.3390/ph17070889
1424-8247