|dc.description.abstract||Malaria persists to proliferate as an economic and social burden in the developing countries despite of a 17% decrease in the estimated number mortalities as reported by the World Health Organization in 2011. In the past decade the annually estimated number of malaria cases has never gone under 216 million, resulting in the mortality rate of more than 8,3 million people, 655 000 in 2011. This worldwide disease is endemic in 109 countries, is dominant in sub-Saharan Africa with 91% of reported cases and 80% of its mortality child and infant related. Malaria is a preventable and curable disease, however Plasmodia mono- and multi-drug resistance towards classic antimalarial drugs such as chloroquine, quinine and sulphadoxine/pyrimethamine etc. has rendered their efficacy useless in certain regions of the world. Five species of Plasmodia infects humans with P. falciparum being the most virulent, prevalent, carries the highest resistant strains towards antimalarial drugs and is responsible for the majority of malaria associated deaths. Plasmodium falciparum resistance towards the last bullet in the gun, artemisinin, has recently been reported in the South-East Asian region. This devastating reality calls for immediate research towards developing novel antimalarials to overcome current predicaments. In the search for novel drugs with antimalarial activity against the increasingly difficult to treat disease, a medicinal chemistry strategy involving the formation of bis-compounds was applied. This formation is the combination of two identical pharmacophores into a single chemical entity to yield a bis-compound. The bis-compound strategy has the potential advantage of bringing forth two pharmacophore moieties to the drugs’ action site, circumventing resistance and restoring the effectiveness of the previous unusable monopharmacophoric drug. Of the various classes of antimalarials available, the antifolates have been used successfully for more than 5 decades in the struggle against malaria. They are potent antimalarials as they inhibit the production of dihydropteroate (DHP) and tetrahydrofolate (THF), two biologically important folate cofactors in the synthesis of parasitic DNA and RNA. Protozoa are incapable of obtaining these folates by means of absorption from their human hosts, and are dependent on the synthesis of the necessary vitamins de novo by means of specific precursors. This metabolic character difference between mammalian and protozoan species results in a perfect drug target for antimalarial therapy. Cycloguanil, the active metabolite of the prodrug proguanil; a dihydrofolate reductase (DHFR) inhibitor, is a commonly used, historically important drug in the 3 treatment of malaria. Its capabilities have been hindered by P. falciparum resistance; nevertheless the folate pathway remains an attractive well recognized target site for drug development. Structural changes to cycloguanils’ pharmacophore can overcome the problem of resistance. The applications of 2,4,6-trichloro-1,3,5-triazine (cyanuric chloride) is nearly endless. It has been studied immensely in a diverse range of applications presenting antibacterial, antitumor and antiparasitic activity. It shares similar chemical properties and biological activity to cycloguanil. By using an appropriate solvent and a hydrochloride acceptor, the chlorine atoms of the cyanuric chloride moiety are easily substituted. Temperature control allows the stepwise formation of mono-, di- or trisubstituted derivatives of triazine with various nucleophiles. The derivatives, including hybrid triazines and triazine related drugs PS15 and WR99210 have revealed promising antimalarial activity against chloroquine sensitive and resistant strains.
The aim of this study was to synthesize a series of disubstituted bistriazines, characterize their physical properties and evaluate their antimalarial activity in vitro in comparison to that of chloroquine.
We successfully synthesized nine disubstituted bistriazines by aromatic nucleophilic substitution at C-2, 4 and 6 with ethylenediamine as linker between the two triazine rings. The structures of the prepared bistriazines were confirmed by nuclear magnetic resonance spectroscopy (NMR), mass spectrometry (MS), infrared spectroscopy (IR) and melting points are reported. The target bistriazines were screened in vitro alongside chloroquine against both chloroquine-sensitive (CQS) 3D7 and chloroquine-resistant (CQR) K1 strains of Plasmodium falciparum. Of the nine bistriazines synthesized, 5 showed activity against both CQS and CQR strains. They were less potent than CQ against the 3D7 strain of P. falciparum. Against, the K1 strain, however, compounds 16 and 17 had potency comparable to that of CQ, while bistriazine 13 was found to be 2-fold more potent. The bistriazines 15 and 19 featuring aniline and morpholine, and aniline substituents on the triazine rings, respectively, were the most active of all synthesized compounds against the K1 strain of P. falciparum. Compounds 15 (EC50 = 0.37 μM) and 19 (EC50 = 0.26 μM) displayed 4- and 6-fold higher potency than CQ (EC50 = 1.67 μM), respectively. The target compounds were screened for cytotoxicity against human fibroblasts (BJ), embryonic kidney (HEK293), liver hepatocytes (Hep G2) and lymphoblast-like (Raji) cell lines 4 alongside staurosporine as reference drug. All the synthesized active bistriazines were found to be selective towards the parasitic cells and non-toxic to the mammalian ones.||en_US