Quest for a potent antimalarial drug lead: Synthesis and evaluation of 6,7-dimethoxyquinazoline-2,4-diamines.

Quinazolines have long been known to exert varied pharmacologic activities that make them suitable for use in treating hypertension, viral infections, tumors, and malaria. Since 2014, we have synthesized approximately 150 different 6,7-dimethoxyquinazoline-2,4-diamines and evaluated their antimalarial activity via structure-activity relationship studies. Here, we summarize the results and report the discovery of 6,7-dimethoxy-N4-(1-phenylethyl)-2-(pyrrolidin-1-yl)quinazolin-4-amine (20, SSJ-717), which exhibits high antimalarial activity as a promising antimalarial drug lead.

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

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.

Anti-babesial activity of a series of 6,7-dimethoxyquinazoline-2,4-diamines (DMQDAs).

Diminazene aceturate (DA), imidocarb dipropionate (ID), atovaquone (ATO), azithromycin (AZI), clindamycin, and quinine have been used to treat animal and human babesiosis for many years, despite their negative effects and rising indications of resistance. Thus, finding anti-babesial compounds that can either treat the infection or lower the dose of drugs given has been a primary objective. Quinazolines are one of the most important nitrogen heterocycles, with a wide range of pharmacological activities including analgesic, anti-inflammatory, sedative-hypnotic, anti-histaminic, anti-cancer, and anti-protozoan properties. The present study investigated the anti-babesial activities of twenty 6,7-dimethoxyquinazoline-2,4-diamines on Babesia spp. One candidate, 6,7-dimethoxy-N4-ethylisopropyl-N2-ethyl(pyridin-4-yl)quinazoline-2,4-diamine (SHG02), showed potent inhibition on Babesia gibsoni in vitro, as well as on B. microti and B. rodhaini in mice. Our findings indicate that the candidate compound SHG02 is promising for further development of anti-babesial drugs and provides a new structure to be explored for developing anti-Babesia therapeutics.

Pharmacodynamics and pharmacokinetics studies of phenoxazinium derivatives for antimalarial agent.

In vivo antimalarial drug candidates screening test was carried out on a series of water-soluble 3,7-bis(dialkylamino)phenoxazin-5-ium derivatives. Among them, 3-(diethylamino)-7-(piperidin-1-yl)phenoxazin-5-ium chloride (SSJ-206) showing highest efficacy was chosen for further pharmcodynamics and pharmacokinetics study. It was supported from these data that the phenoxazinium salts, SSJ-206, would be one of hopeful candidates as an oral antimalarial drug.

In vitro and in vivo characterization of the antimalarial lead compound SSJ-183 in Plasmodium models.

The objective of this work was to characterize the in vitro (Plasmodium falciparum) and in vivo (Plasmodium berghei) activity profile of the recently discovered lead compound SSJ-183. The molecule showed in vitro a fast and strong inhibitory effect on growth of all P. falciparum blood stages, with a tendency to a more pronounced stage-specific action on ring forms at low concentrations. Furthermore, the compound appeared to be equally efficacious on drug-resistant and drug-sensitive parasite strains. In vivo, SSJ-183 showed a rapid onset of action, comparable to that seen for the antimalarial drug artesunate. SSJ-183 exhibited a half-life of about 10 hours and no significant differences in absorption or exposure between noninfected and infected mice. SSJ-183 appears to be a promising new lead compound with an attractive antimalarial profile.

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

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.

Fluorinated rhodacyanine (SJL-01) possessing high efficacy for visceral leishmaniasis (VL).

Anti-Leishmania in vitro and in vivo activities of various rhodacyanine derivatives have been examined. Among them, the fluorinatied variant SJL-01 (8) showed IC(50) of 0.011 microM against Leishmania donovani strain MHOM/ET/67/L82 (selective index of >15000) and 95-97% inhibition against L. donovani strain MHOM/ET/67/HU in female BALB/c mice by 1.3-12.5 mg/kg x 5 iv administrations. Negative results on chromosomal aberration test and in vitro micronucleus test suggest that compound 8 is a hopeful candidate for visceral leishmaniasis (VL).

Taste disorder involving Hunter's glossitis following total gastrectomy.

We treated five patients with Hunter's glossitis following total gastrectomy. The major complaints of the patients were taste disorder and abnormal glossal sensation. In all five cases, the patient's tongue was red and smooth, and laboratory testing showed the presence of macrocytic anemia and decreased serum concentration of vitamin B12 (cyanocobalamin). Gustometry was carried out in four cases and the results documented the presence of taste disorder. All five patients were treated by administration of vitamin B12, which led to improvements in the appearance of the tongue, the patients' subjective complaints and the results of taste testing. When patients present with a red, smooth tongue, Hunter's glossitis (which can easily be improved by administration of vitamin B12) should be considered in the differential diagnosis.