SYNTHESIS AND PRECLINICAL EVALUATION OF NOVEL CHALCONE-DERIVED HYBRIDS AS DUAL-ACTION ANTIMALARIAL AND ANTI-INFLAMMATORY AGENTS

Background: Malaria remains a major global health burden, with severe forms such as cerebral malaria contributing significantly to mortality and long-term neurological complications. While existing antimalarial therapies are effective in reducing parasite load, they often fail to adequately address the host-driven inflammatory responses that underlie severe disease manifestations. This therapeutic gap highlights the need for multifunctional agents capable of targeting both parasitic infection and inflammation-related pathology. Objective: The study aimed to develop and preclinically evaluate novel chalcone-derived hybrid compounds with dual antimalarial and anti-inflammatory activity, focusing on parasite clearance and modulation of inflammation relevant to cerebral involvement. Methods:A descriptive preclinical study was conducted over two months in Dera Ghazi Khan. Novel chalcone-derived hybrids were synthesized and structurally characterized using standard spectroscopic techniques. Antimalarial activity was assessed through in vitro Plasmodium falciparum growth inhibition assays, while anti-inflammatory effects were evaluated using cytokine profiling and histopathological assessment in an established inflammatory model. Data were analyzed using parametric statistical tests, with significance set at p < 0.05. Results: The synthesized compounds demonstrated varying degrees of antimalarial efficacy, with the most active hybrid achieving parasite inhibition comparable to the reference drug and exhibiting a low IC₅₀ value. Treated groups showed marked reductions in tumor necrosis factor-α and interleukin-6 levels compared to controls. Histopathological findings supported these results, revealing significantly reduced inflammatory changes in brain tissue among treated groups. A strong inverse correlation was observed between parasite inhibition and inflammatory marker levels. Conclusion: Chalcone-derived hybrid compounds exhibited promising dual-action effects by effectively inhibiting parasite growth and attenuating inflammation-associated responses. These findings supported the potential of multifunctional chalcone-based agents as candidates for further preclinical development targeting both infection and inflammation in malaria.