Exploration of a Novel Physicochemical Property Space for the Development of Antimalarial Drugs

INTRODUCTION: Malaria remains a major global health burden, with rising resistance to artemisinin and most current therapies, alongside emerging parasite species and genetic mutations that undermine disease control efforts. Identifying drug candidates with favorable physicochemical profiles is crucial for improving success rates in antimalarial drug discovery. METHODS: A comprehensive dataset comprising 52 approved and clinical-stage antimalarial drugs and 1,708 antimalarial research compounds was compiled. Their physicochemical properties were analyzed to characterize distribution patterns and identify parameters that distinguish successful drugs from research compounds. RESULTS: Four key parameters-molecular weight (MW), calculated partition coefficient (cLogP), topological polar surface area (TPSA), and fraction of sp3-hybridized carbons (Fsp3)-showed significant differences between drugs and research compounds. These parameters enabled the definition of an antimalarial-specific physicochemical space described by 248.71 ≤ MW ≤ 535.51, 1.86 ≤ cLogP ≤ 5.21, 28.16 ≤ TPSA ≤ 100.52, and 0.11 ≤ Fsp3 ≤ 1. Approximately 75% of approved or clinical antimalarial drugs fall within this space, compared with 49% of research compounds and 46% of high-potency candidates. DISCUSSION: These findings highlight a distinct and data-driven physicochemical profile associated with successful antimalarial agents, underscoring limitations of general drug-likeness rules such as Lipinski's Rule of Five (Ro5). The proposed space enhances compound prioritization by focusing on property ranges linked to clinical success. However, the analysis is constrained by available datasets and may not fully reflect emerging chemotypes or novel therapeutic modalities. CONCLUSION: This study defines an antimalarial-specific physicochemical space that can support compound prioritization and guide optimization efforts during antimalarial drug discovery.