Chalcone derivatives for antimalarial drug discovery: drug-likeness evaluation and chemical space analysis

Abstract

Introduction: Malaria remains a major global health challenge, and the emergence of artemisinin resistance demands structurally novel therapeutic candidates. High-quality, curated chemical datasets are a prerequisite for robust computational antimalarial drug discovery; chalcone is one of the most pharmacologically active classes of antiparasitic compounds, yet no standardized, systematically curated dataset with annotated physicochemical properties exists for this scaffold. The absence of such a resource constrains the development of robust quantitative structure-activity relationship (QSAR) and machine learning models for chalcone antimalarial drug discovery. Materials and methods: This study describes the systematic compilation, rigorous curation, and comprehensive physicochemical profiling of chalcone derivatives with experimentally validated antiplasmodial activity against Plasmodium falciparum. An initial dataset of 392 compounds was compiled from 19 peer-reviewed sources. A stringent curation pipeline encompassing removal of non-quantitative entries, duplicate resolution, and bioactivity classification yielded a final binary dataset of 251 non-redundant compounds: 55 active (pIC50 ≥ 6.0, where pIC50 is the negative logarithm of the half-maximal inhibitory concentration 21.9%) and 196 inactive (pIC50 < 5.0; 78.1%). Results: Mann–Whitney U tests with Bonferroni correction revealed highly significant differences across all six descriptors (all p < 10−13). Active compounds exhibited substantially elevated molecular weight (538.17 ± 56.34 Da vs. 346.85 ± 97.41 Da; p = 4.38 × 10−21), lipophilicity (LogP) (6.98 ± 1.28 vs. 4.54 ± 1.09; p = 1.09 × 10−21), topological polar surface area (80.29 ± 11.86 Å2 vs. 52.46 ± 24.89 Å2; p = 1.01 × 10−17), and number of rotatable bond (nRB) count (9.25 ± 1.82 vs. 5.87 ± 2.28) relative to inactive compounds. Notably, 98.2% of active compounds violated Lipinski’s Rule of Five, with 73.7% of dual molecular weight (MW) and LogP violators demonstrating antiplasmodial activity, compared to only 0.7% of fully Lipinski-compliant compounds. Despite systematic Lipinski violations, 74.5% of active compounds satisfied Veber oral bioavailability criteria (TPSA ≤ 140 Å2, where topological polar surface area, nRB ≤ 10). Principal component analysis (PCA) of six descriptors explained 81.6% of total variance principal component 1 (PC1): 62.4%; principal component 2 (PC2): 19.2%, confirming that active chalcones occupy a distinct, high-MW, high-LogP chemical space. Conclusions: These findings suggest that, for chalcone-based antimalarial scaffolds, rigid adherence to Lipinski criteria may inadvertently deprioritize compounds with genuine antiplasmodial potential, demonstrating that conventional drug-likeness filters are poorly calibrated for this chemotype.