Antiplasmodial activity of [(aryl)arylsulfanylmethyl]Pyridine.
A series of [(aryl)arylsufanylmethyl]pyridines (AASMP) have been synthesized. These compounds inhibited hemozoin formation, formed complexes (K(D) = 12 to 20 muM) with free heme (ferriprotoporphyrin IX) at a pH close to the pH of the parasite food vacuole, and exhibited antimalarial activity in vitro. The inhibition of hemozoin formation may develop oxidative stress in Plasmodium falciparum due to the accumulation of free heme. Interestingly, AASMP developed oxidative stress in the parasite, as evident from the decreased level of glutathione and increased formation of lipid peroxide, H(2)O(2), and hydroxyl radical (.OH) in P. falciparum. AASMP also caused mitochondrial dysfunction by decreasing mitochondrial potential (DeltaPsim) in malaria parasite, as measured by both flow cytometry and fluorescence microscopy. Furthermore, the generation of .OH may be mainly responsible for the antimalarial effect of AASMP since .OH scavengers such as mannitol, as well as spin trap alpha-phenyl-n-tertbutylnitrone, significantly protected P. falciparum from AASMP-mediated growth inhibition. Cytotoxicity testing of the active compounds showed selective activity against malaria parasite with selectivity indices greater than 100. AASMP also exhibited profound antimalarial activity in vivo against chloroquine resistant P. yoelii. Thus, AASMP represents a novel class of antimalarial.
Kumar
Sanjay
S
Drug Target Discovery and Development Division, Medicinal and Process Chemistry Division, Central Drug Research Institute, Lucknow-226001, UP, India.
Das
Sajal Kumar
SK
Dey
Sumanta
S
Maity
Pallab
P
Guha
Mithu
M
Choubey
Vinay
V
Panda
Gautam
G
Bandyopadhyay
Uday
U
D000818:Animals; D000962:Antimalarials / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D001573:Benzoin / Q000378:metabolism; D004912:Erythrocytes / Q000187:drug effects / Q000469:parasitology; D006427:Hemin / Q000378:metabolism; D006801:Humans; D008288:Malaria / Q000188:drug therapy* / Q000469:parasitology; D051379:Mice; D008807:Mice, Inbred BALB C; D018384:Oxidative Stress; D021261:Parasitic Sensitivity Tests; D010963:Plasmodium falciparum / Q000187:drug effects*; D010967:Plasmodium yoelii / Q000187:drug effects*; D011725:Pyridines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology* / Q000627:therapeutic use
D000962:Antimalarials; D011725:Pyridines; D006427:Hemin; D001573:Benzoin