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Naturally occurring cobalamins have antimalarial activity.

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New vitamin B12 derivatives show potent inhibition of beta-haematin formation, a key process in malaria parasite survival. These cobalamins offer a promising avenue for developing novel antimalarial chemotherapeutic agents against drug-resistant malaria.

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Area of Science:

  • Biochemistry
  • Parasitology
  • Medicinal Chemistry

Background:

  • Antimalarial drug resistance necessitates novel chemotherapeutic agents.
  • Beta-haematin (synthetic haemozoin) formation is a critical target for antimalarial drugs.
  • Vitamin B12 (cobalamin) derivatives are explored for their potential antimalarial activity.

Purpose of the Study:

  • To evaluate the inhibitory effects of vitamin B12 derivatives on beta-haematin formation.
  • To compare the efficacy of cobalamins with chloroquine in inhibiting haemozoin formation.
  • To investigate the antimalarial activity and food vacuole accumulation of cobalamins.

Main Methods:

  • Assessed beta-haematin formation inhibition by various cobalamins (Adenosylcobalamin, Methylcobalamin, Aquocobalamin, Cyanocobalamin) and chloroquine.
  • Determined antimalarial activity of cobalamins in vitro.
  • Investigated cobalamin accumulation in the Plasmodium falciparum food vacuole via pH trapping.

Main Results:

  • Adenosylcobalamin, Methylcobalamin, and Aquocobalamin were ~40 times more effective inhibitors of beta-haematin formation than chloroquine.
  • Cyanocobalamin showed slightly greater inhibition than chloroquine; dicyanocobinamide had no effect.
  • Cobalamins exhibit antimalarial activity, with Adenosylcobalamin > Methylcobalamin > Aquocobalamin > Cyanocobalamin, though less than chloroquine or quinine.
  • Aquocobalamin accumulates in the parasite food vacuole by pH trapping, unlike other tested cobalamins.

Conclusions:

  • Vitamin B12 derivatives, particularly Adenosylcobalamin and Methylcobalamin, are potent inhibitors of beta-haematin formation.
  • Cobalamins demonstrate antimalarial properties by interfering with haemozoin synthesis.
  • Targeting the unique cobalamin-dependent methionine synthase in Plasmodium falciparum offers a potential strategy for novel antimalarial drug development.