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 IC 50 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.

Selective induction of oxidative stress in cancer cells via synergistic combinations of agents targeting redox homeostasis

“…14,24 Methylene blue (MB) was purchased from ChemSupply (Australia). Clofazimine (CFZ) was purchased from Sigma Aldrich.…”

Copper‐Catalyzed C−H Oxygenation of Benzoxepine‐4‐carboxylates: Facile Synthesis and Photophysical Properties of Naphtho[2,1‐d]oxazoles and Benzo[c]phenoxazines

“…The benzo[ a ]phenoxazines Meldola′s blue, Nile red, and Nile blue are cationic fluorophores that have been used for the histochemical detection of nucleic acids . Furthermore, benzo[ a ]phenoxazine derivatives have been reported as P‐glycoprotein inhibitors, drug candidates for malaria, potent anti‐proliferative agents, antimicrobial photosensitizers, and lysosome trackers for cell imaging . Benzo[ b ]phenoxazine derivatives such as 3‐imino‐3 H ‐benzo[ b ]phenoxazin‐11‐amine fluoresce in the range 760–790 nm .…”

Synthesis of new tetrahydropyridinylidene ammonium salts and their antiprotozoal potency

“…Several 4-aminopyridines showed antimalarial activity [4][5][6]. We, therefore, prepared a series of new pyridinylidene salts with differing 4-amino substitution and investigated them for their activities against Plasmodium falciparum and T. b. rhodesiense as well as for their cytotoxicity.…”