Synthesis and Antimalarial Activity of Lawsone Mannich Base Derivatives

Abstract:

Introduction: The emergence of multi-drug resistant strains of Plasmodium falciparum has increasingly become a serious health problem worldwide. To address this challenging issue, there is an urgent need to discover and develop novel and potent antimalarial agents. Materials and Methods: A new series of lawsone Mannich base derivatives were synthesized, characterized (IR, NMR and Mass) and evaluated for in vitro for antimalarial activity against chloroquine (CQ)-sensitive and CQ-resistant strains of P. falciparum. Results and Discussion: Among synthesized compounds, five compounds showed good antimalarial activity against both chloroquine (CQ)-sensitive (3D-7) and -resistant (RKL- 2) strains of P. falciparum, which, however, was considerably less than that of the standard reference drug, CQ. The antimalarial activity of these five compounds was found better against sensitive (IC₅₀ = 0.411-0.502 μg/ml) strain than the resistant (IC₅₀ = 1.391-2.394 μg/ml) one. The IC₅₀ values for CQ were 0.044 μg/ml and 0.216 μg/ml against sensitive and resistant strains of P. falciparum, respectively. SAR study suggests that antimalarial potential of lawsone structural scaffold can be modulated by different substitution pattern like Mannich base substitution (alkyl/aryl/heteroaryl substituted aminoalkyl moiety) at the C-3 position of 1,4-naphthoquinone ring system. Conclusion: Owing to their antimalarial effectiveness, lawsone derived aminonaphthoquinones can be used as lead structure(s) in the development of yet more potent antimalarial agents.

Key words: Lawsone, Mannich bases, Aminonaphthoquinone, Plasmodium falciparum, Resistant malaria.