Novel synthetic route for antimalarial benzo[a]phenoxazine derivative SSJ-183 and two active metabolites

Yuki Mizukawa; Jian-Feng Ge; Abu Bakar Md; Isamu Itoh; Christian Scheurer; Sergio Wittlin; Reto Brun; Hiroyuki Matsuoka; Masataka Ihara

doi:10.1016/j.bmc.2014.04.066

Novel synthetic route for antimalarial benzo[a]phenoxazine derivative SSJ-183 and two active metabolites

Bioorg Med Chem. 2014 Jul 15;22(14):3749-52. doi: 10.1016/j.bmc.2014.04.066. Epub 2014 May 10.

Authors

Yuki Mizukawa¹, Jian-Feng Ge², Abu Bakar Md³, Isamu Itoh¹, Christian Scheurer⁴, Sergio Wittlin⁴, Reto Brun⁴, Hiroyuki Matsuoka⁵, Masataka Ihara⁶

Affiliations

¹ Drug Discovery Science Research Center, Hoshi University, 2-4-41 Ebara, Shinagawa, Tokyo 142-8501, Japan; Synstar Japan Co., Ltd, Orbic Bldg 3F, 2-9-46 Sakaecho, Odawara 250-0011, Japan.
² 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.
³ Drug Discovery Science Research Center, Hoshi University, 2-4-41 Ebara, Shinagawa, Tokyo 142-8501, Japan; Center for Advanced Research in Sciences, University of Dhaka, Bangladesh.
⁴ Swiss Tropical and Public Health Institute, Socinstrasse 57, 4002 Basel, Switzerland; University of Basel, CH-4003 Basel, Switzerland.
⁵ School of Medicine, Department of Infection and Immunity, Division of Medical Zoology, Jichi Medical University, 3311-1 Yakushiji, Shimotsuke-shi 329-0498, Japan.
⁶ Drug Discovery Science Research Center, Hoshi University, 2-4-41 Ebara, Shinagawa, Tokyo 142-8501, Japan. Electronic address: m-ihara@hoshi.ac.jp.

PMID: 24856305
DOI: 10.1016/j.bmc.2014.04.066

Abstract

A productive synthesis of benzo[a]phenoxazine derivative SSJ-183 (1), a promising lead for antimalarial agents, was developed using a one pot procedure. Furthermore, N-deethylated metabolite 3 and bis-N,N-deethylated metabolite 4 were synthesized by the application of the method. The metabolites 3 and 4 showed comparable and ∼2-fold increased activities against drug-sensitive and drug-resistant Plasmodium falciparum parasites.

Keywords: Antimalarial; Benzo[a]phenoxazine; Drug-sensitive and drug-resistant; Metabolites; Plasmodium falciparum.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Antimalarials / chemical synthesis
Antimalarials / metabolism
Antimalarials / pharmacology*
Dose-Response Relationship, Drug
Microbial Sensitivity Tests
Molecular Structure
Oxazines / chemical synthesis
Oxazines / metabolism
Oxazines / pharmacology*
Parasitic Sensitivity Tests
Plasmodium falciparum / drug effects*
Pyridines / chemical synthesis
Pyridines / metabolism
Pyridines / pharmacology*
Structure-Activity Relationship

Substances

Antimalarials
Oxazines
Pyridines
SSJ 183