Search

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-N(4)-(1-phenylethyl)-2-(pyrrolidin-1-yl)quinazolin-4-amine (20, SSJ-717), which exhibits high antimalarial activity as a promising antimalarial drug lead.

Background Basic blue 3 is a promising anti-malarial lead compound based on the π-delocalized lipophilic cation hypothesis. Its derivatives with nitrogen atoms bonded to carbon atoms at the 3- and 7-positions on the phenoxazine ring were previously shown to exert potent antiprotozoal activity against Plasmodium falciparum, Trypanosoma cruzi, Trypanosoma brucei rhodesiense, and Leishmania donovani parasites in vitro. However, compounds with nitrogen modification at the 10-position on the phenoxazine ring were not evaluated. Methods Six acylphenoxazine derivatives (ITT-001 to 006) with nitrogen modification at the 10-position on the phenoxazine ring, which were synthesized from basic blue 3, were characterized and evaluated for anti-malarial activity in vitro with an automated haematology analyzer (XN-30) and light microscopy. Intensity of self-fluorescence was measured using a fluorometer. Localization of basic blue 3 was observed by fluorescence microscopy. Cytotoxicity was evaluated using human cell lines, HEK293T and HepG2 cells. Finally, anti-malarial activity was evaluated in a rodent malaria model. Results All the six derivatives showed anti-malarial efficacy even against chloroquine-, pyrimethamine-, and artemisinin-resistant field isolates similar to the sensitive strains and isolates in vitro. The efficacy of basic blue 3 was the strongest, followed by that of ITT-001 to 004 and 006, while that of ITT-005 was the weakest. Basic blue 3 showed strong self-fluorescence, whereas ITT derivatives had five- to tenfold lower intensity than that of basic blue 3, which was shown by fluorescence microscopy to be selectively accumulated in the plasmodial cytoplasm. In contrast, ITT-003, 004, and 006 exhibited the lowest cytotoxicity in HEK293T and HepG2 cells in vitro and the highest selectivity between anti-malarial activity and cytotoxicity. The in vivo anti-malarial assay indicated that oral administration of ITT-004 was the most effective against the rodent malaria parasite, Plasmodium berghei NK65 strain. Conclusions The six ITT derivatives were effective against chloroquine- and pyrimethamine-resistant strains and artemisinin-resistant field isolates as well as the sensitive ones. Among them, ITT-004, which had high anti-malarial activity and low cytotoxicity in vitro and in vivo, is a promising anti-malarial lead compound. Electronic supplementary material The online version of this article (10.1186/s12936-019-2873-0) contains supplementary material, which is available to authorized users.

Sarah Schleiferböck,1,2 Christian Scheurer,1,2 Masataka Ihara,3,4 Isamu Itoh,3,4 Ian Bathurst,5,† Jeremy N Burrows,5 Pascal Fantauzzi,5 Julie Lotharius,5 Susan A Charman,6 Julia Morizzi,6 David M Shackleford,6 Karen L White,6 Reto Brun,1,2 Sergio Wittlin1,21Swiss Tropical and Public Health Institute, Basel, 2University of Basel, Basel, Switzerland; 3Drug Discovery Science Research Center, Hoshi University, Shinagawa, Tokyo, Japan; 4Synstar Japan Co, Ltd, Odawara, Japan; 5Medicines for Malaria Venture, Geneva, Switzerland; 6Centre for Drug Candidate Optimisation, Monash Institute of Pharmaceutical Sciences, Parkville, VIC, Australia †Ian Bathurst passed away on 26 June 2011Abstract: 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.Keywords: antimalarial studies, cross-resistance, stage-specificity, Plasmodium falciparum

The Sendai Institute of Heterocyclic Chemistry, No. 53, Kawauchisanjunin-machi, Sendai 980, Japan An ene reaction has been observed on thermolysis of 1-(N-allyl-N-benzy1-2-amino­ethyl)-5-methoxy-1-methylbenzocyclobotene (I). To this paper we also describe the formation of indenes and indanes from 5-metboxy-1-methyl-1-p-tolnenesulfonylmethyl­benzocyclobutene (VII) by rearrangement.