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Antimicrobial Agents and Chemotherapy, August 2007, p. 2842-2847, Vol. 51, No. 8
0066-4804/07/$08.00+0     doi:10.1128/AAC.00288-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

2-tert-Butyl-8-Quinolinamines Exhibit Potent Blood Schizontocidal Antimalarial Activity via Inhibition of Heme Crystallization{triangledown}

Nguyen Tien Huy,1,2 Keisuke Mizunuma,1 Kirandeep Kaur,3 Nguyen Thanh Thuy Nhien,1 Meenakshi Jain,3 Dinh Thanh Uyen,1 Shigeharu Harada,1 Rahul Jain,3* and Kaeko Kamei1*

Department of Applied Biology, Kyoto Institute of Technology, Matsugasaki, Sakyo-ku, Kyoto 606-8585, Japan,1 Venture Laboratory, Kyoto Institute of Technology, Matsugasaki, Sakyo-ku, Kyoto 606-8585, Japan,2 Department of Medicinal Chemistry, National Institute of Pharmaceutical Education and Research, Sector 67, S.A.S. Nagar, Punjab 160 062, India3

Received 27 February 2007/ Returned for modification 2 May 2007/ Accepted 5 June 2007

We have recently reported that the attachment of a bulky metabolically stable tert-butyl group at the C-2 position of a quinoline ring in primaquine results in a tremendous improvement in the blood schizontocidal antimalarial activity of 8-quinolinamine. Because free heme released from hemoglobin catabolism in a malarial parasite is highly toxic, the parasite protects itself mainly by crystallization of heme into insoluble nontoxic hemozoin. We now demonstrate the ability of 2-tert-butylprimaquine to inhibit in vitro beta-hematin formation, to form a complex with heme with a stoichiometry of 1:1, and to enhance heme-induced hemolysis. The results described herein indicate that a major improvement in the blood-schizontocidal antimalarial activity of 2-tert-butylprimaquine might be due to a disturbance of heme catabolism pathway in the malarial parasite.

* Corresponding author. Mailing address for Kaeko Kamei: Department of Applied Biology, Kyoto Institute of Technology, Matsugasaki, Sakyo-ku, Kyoto 606-8585, Japan. Phone: 81-75-724-7553. Fax: 81-75-724-7541. E-mail: kame{at}kit.ac.jp. Mailing address for Rahul Jain: Department of Medicinal Chemistry, National Institute of Pharmaceutical Education and Research, Sector 67, S.A.S. Nagar, Punjab 160 062, India. Phone: 91-172-221-4682. Fax: 91-172-221-4692. E-mail: rahuljain{at}niper.ac.in

{triangledown} Published ahead of print on 11 June 2007.

Antimicrobial Agents and Chemotherapy, August 2007, p. 2842-2847, Vol. 51, No. 8
0066-4804/07/$08.00+0     doi:10.1128/AAC.00288-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.





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