title: Discovery of Novel Benzo[a]phenoxazine SSJ-183 as a Drug Candidate for Malaria.
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.
authors.affiliation: 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.
authors.forename: Jian-Feng
authors.initials: JF
authors.lastname: Ge
authors.affiliation: Drug Discovery Science Research Center, Hoshi University, 2-4-41 Ebara, Shinagawa, Tokyo 142-8501, Japan.
authors.forename: Chika
authors.initials: C
authors.lastname: Arai
authors.affiliation: Drug Discovery Science Research Center, Hoshi University, 2-4-41 Ebara, Shinagawa, Tokyo 142-8501, Japan.
authors.forename: Mei
authors.initials: M
authors.lastname: Yang
authors.affiliation: Drug Discovery Science Research Center, Hoshi University, 2-4-41 Ebara, Shinagawa, Tokyo 142-8501, Japan.
authors.forename: Abu
authors.initials: A
authors.lastname: Bakar Md
authors.affiliation: Drug Discovery Science Research Center, Hoshi University, 2-4-41 Ebara, Shinagawa, Tokyo 142-8501, Japan.
authors.forename: Jun
authors.initials: J
authors.lastname: Lu
authors.affiliation: 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.
authors.forename: Nasser S M
authors.initials: NS
authors.lastname: Ismail
authors.affiliation: Swiss Tropical and Public Health Institute, Socinstrasse 57, CH-4002 Basel, and University of Basel, Basel, Switzerland.
authors.forename: Sergio
authors.initials: S
authors.lastname: Wittlin
authors.affiliation: Swiss Tropical and Public Health Institute, Socinstrasse 57, CH-4002 Basel, and University of Basel, Basel, Switzerland.
authors.forename: Marcel
authors.initials: M
authors.lastname: Kaiser
authors.affiliation: Swiss Tropical and Public Health Institute, Socinstrasse 57, CH-4002 Basel, and University of Basel, Basel, Switzerland.
authors.forename: Reto
authors.initials: R
authors.lastname: Brun
authors.affiliation: Centre for Drug Candidate Optimisation, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville Campus, 381 Royal Parade, Parkville, Victoria 3052, Australia.
authors.forename: Susan A
authors.initials: SA
authors.lastname: Charman
authors.affiliation: Centre for Drug Candidate Optimisation, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville Campus, 381 Royal Parade, Parkville, Victoria 3052, Australia.
authors.forename: Tien
authors.initials: T
authors.lastname: Nguyen
authors.affiliation: Centre for Drug Candidate Optimisation, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville Campus, 381 Royal Parade, Parkville, Victoria 3052, Australia.
authors.forename: Julia
authors.initials: J
authors.lastname: Morizzi
authors.affiliation: Synstar Japan Co., Ltd., Tokyo Tech Yokohama Venture Plaza W401, 4259-3 Nagatsuta-cho, Midori-ku, Yokohama, 226-8510, Japan.
authors.forename: Isamu
authors.initials: I
authors.lastname: Itoh
authors.affiliation: Drug Discovery Science Research Center, Hoshi University, 2-4-41 Ebara, Shinagawa, Tokyo 142-8501, Japan.
authors.forename: Masataka
authors.initials: M
authors.lastname: Ihara
keywords: Antimalarial activity; Plasmodium berghei; Plasmodium falciparum; benzo[a]phenoxazine; oral administration