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Antimicrobial Agents and Chemotherapy, February 2008, p. 705-715, Vol. 52, No. 2
0066-4804/08/$08.00+0     doi:10.1128/AAC.00898-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

Antiplasmodial Activity of [(Aryl)arylsulfanylmethyl]Pyridine{triangledown} ,{dagger},{ddagger}

Sanjay Kumar,1 Sajal Kumar Das,2 Sumanta Dey,3 Pallab Maity,3 Mithu Guha,3 Vinay Choubey,1 Gautam Panda,2* and Uday Bandyopadhyay3*

Drug Target Discovery and Development Division,1 Medicinal and Process Chemistry Division, Central Drug Research Institute, Lucknow-226001, UP, India,2 Division of Infectious Diseases and Immunology, Indian Institute of Chemical Biology, 4, Raja S. C. Mullick Road, Jadavpur, Kolkata 700032, West Bengal, India3

Received 10 July 2007/ Returned for modification 6 August 2007/ Accepted 29 October 2007

A series of [(aryl)arylsufanylmethyl]pyridines (AASMP) have been synthesized. These compounds inhibited hemozoin formation, formed complexes (KD = 12 to 20 µM) 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, H2O2, and hydroxyl radical (·OH) in P. falciparum. AASMP also caused mitochondrial dysfunction by decreasing mitochondrial potential ({Delta}{Psi}m) 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.

* Corresponding authors. Mailing address for U. Bandyopadhyay: Division of Infectious Diseases and Immunology, Indian Institute of Chemical Biology, 4, Raja S. C. Mullick Road, Jadavpur, Kolkata 700032, West Bengal, India. Phone: 91-33-247330491. Fax: 91-33-24735197. E-mail: ubandyo_1964{at}yahoo.com. Mailing address for G. Panda: Medicinal and Process Chemistry Division, Central Drug Research Institute, Lucknow-226001, UP, India. Fax: 91-522-2612411. Phone: 91-522-2623405. E-mail: gautam.panda{at}gmail.com

{triangledown} Published ahead of print on 19 November 2007.

{dagger} Supplemental material for this article may be found at http://aac.asm.org/.

{ddagger} Central Drug Research Institute communication 7191.

Antimicrobial Agents and Chemotherapy, February 2008, p. 705-715, Vol. 52, No. 2
0066-4804/08/$08.00+0     doi:10.1128/AAC.00898-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.





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