2. Academic Validation
  3. Discovery of Novel Benzo[a]phenoxazine SSJ-183 as a Drug Candidate for Malaria

Discovery of Novel Benzo[a]phenoxazine SSJ-183 as a Drug Candidate for Malaria

  • ACS Med Chem Lett. 2010 Jul 12;1(7):360-4. doi: 10.1021/ml100120a.
Jian-Feng Ge 1,  Chika Arai 2,  Mei Yang 2,  Abu Bakar Md 2,  Jun Lu 2,  Nasser S M Ismail 3,  Sergio Wittlin 4,  Marcel Kaiser 4,  Reto Brun 4,  Susan A Charman 5,  Tien Nguyen 5,  Julia Morizzi 5,  Isamu Itoh 6,  Masataka Ihara 2
Affiliations

Affiliations

  • 1 Drug Discovery Science Research Center, Hoshi University, 2-4-41 Ebara, Shinagawa, Tokyo 142-8501, Japan ; College of Chemistry, Chemical Engineering and Materials Science, Soochow University, Suzhou 215006, China.
  • 2 Drug Discovery Science Research Center, Hoshi University, 2-4-41 Ebara, Shinagawa, Tokyo 142-8501, Japan.
  • 3 Drug Discovery Science Research Center, Hoshi University, 2-4-41 Ebara, Shinagawa, Tokyo 142-8501, Japan ; Pharmaceutical Chemistry Department, Faculty of Pharmacy Ain Shams University, Elkhalifa AlMaamoon Street, 11566 Abbasseya, Cairo, Egypt.
  • 4 Swiss Tropical and Public Health Institute, Socinstrasse 57, CH-4002 Basel, and University of Basel, Basel, Switzerland.
  • 5 Centre for Drug Candidate Optimisation, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville Campus, 381 Royal Parade, Parkville, Victoria 3052, Australia.
  • 6 Synstar Japan Co., Ltd., Tokyo Tech Yokohama Venture Plaza W401, 4259-3 Nagatsuta-cho, Midori-ku, Yokohama, 226-8510, Japan.
PMID: 24900219 DOI: 10.1021/ml100120a
Abstract

Malaria is a serious infectious disease caused by protozoan parasites in tropical and subtropical regions. Even inhabitants of temperate zones are exposed to the danger of malaria Infection because of travel and global warming. Novel, effective, safe, and inexpensive drugs are required to treat malaria and contribute to the global goal of eradication. A search for new antimalarial agents has been performed by the synthesis of new benzo[a]phenoxazines, followed by biological evaluations. The derivative SSJ-183 (5), having a 4-aminopyridine group, showed an IC50 value against Plasmodium falciparum of 7.6 nM and a selectivity index of >7300. Cure was achieved by three oral doses of 5 at 100 mg/kg to mice infected with the Plasmodium berghei ANKA strain. The safety of 5 was supported by acute toxicity testing in mice with single doses up to 2000 mg/kg po, chromosome aberration test, in vitro as well as in vivo micronucleus tests, and phototoxicity studies in mice. Thus, 5 is a promising candidate as a new antimalarial agent.

Keywords

Antimalarial activity; Plasmodium berghei; Plasmodium falciparum; benzo[a]phenoxazine; oral administration.

Figures