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 (IC 50 = 0.411-0.502 μg/ml) strain than the resistant (IC 50 = 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.

Synthesis and Evaluation of 2-Hydroxy-1,4-naphthoquinone Derivatives as Potent Antimalarial Agents

“…Recently, ten lawsone derivatives, including 3-aryl, heteroaryl and alkyl substituted aminomethyl moieties, were synthesized by Mannich reaction. 26) Among them, five Mannich bases with aryl substituents at R 1 and R 2 , displayed positive antimalarial activity against both chloroquine (CQ)sensitive and chloroquine (CQ)-resistant strains of Plasmodium falciparum with IC 50 values in the range of 0.41-0.50 g/mL and 1.39-2.39 g/mL, respectively. However, only the naphthoquinone, possessing an alkyl (n-propyl) amino group at R 1 , was synthesized and found to be inactive.…”

“…Consequently, our present study was consistent to the previous work by the use of the same building block of 3-substituted aminomethyl-1,4naphthoquinone. 26) It was extended further in terms of varying the substituents in order to obtain more promising antimalarial candidates. Sixteen 3-substituted-aminomethyl-2-hydroxy-1,4-naphthoquinones (1-16) were prepared using a Mannich reaction to introduce two substituents at R 1 and R 2 .…”

“…[20][21][22] In the recently work, five Mannich bases with aryl substituents at R 1 and R 2 were reported to display positive antimalarial activity. 26) It was also demonstrated that naphthoquinones with aryl moieties (phenyl or NO 2 -, F-, OH-phenyl groups) at position 3 were more potentially important for the activity than other derivatives with heterocyclic or small alkyl groups. In addition, only the alkyl substituted naphthoquinone analogue with the three-carbon alkyl (n-propyl) group at R 1 was explored and turned out to be inactive.…”

“…Interestingly, all n-butyl substituted aminomethyl naphthoquinones (1-3) displayed effective activity whereas the similar analogue with a n-propyl group was previously reported as an inactive agent. 26) The…”

“…The aminomethyl linker at position 3 between the lawsone skeleton and substituents was an important counterpart for this activity. 26)…”