Despite many efforts, malaria remains among the most problematic infectious diseases worldwide, mainly due to the development of drug resistance by P. falciparum. Over the past decade, new essential pathways have been emerged to fight against malaria. Among them, epigenetic processes and mitochondrial metabolism appear to be important targets. This review will focus on recent evolutions concerning worldwide efforts to conceive, synthesize and evaluate new drug candidates interfering selectively and efficiently with these two targets and pathways. The focus will be on compounds/scaffolds that possess biological/pharmacophoric properties on DNA methyltransferases and HDAC’s for epigenetics, and on cytochrome bc1 and dihydroorotate dehydrogenase for mitochondrion.
The first effective
synthetic approach to naphthofuroquinones via
a reaction involving lawsone, various aldehydes, and three isocyanides
under microwave irradiation afforded derivatives in moderate to good
yields. In addition, for less-reactive aldehydes, two naphtho-enaminodione
quinones were obtained for the first time, as result of condensation
between lawsone and isocyanides. X-ray structure determination for 9 and 2D-NMR spectra of 28 confirmed the obtained
structures. All compounds were evaluated for their anti-infectious
activities against Plasmodium falciparum, Leishmania donovani, and Mycobacterium tuberculosis. Among the naphthofuroquinone
series, 17 exhibited comparatively the best activity
against P. falciparum (IC50 = 2.5 μM) and M. tuberculosis (MIC = 9 μM) with better (P. falciparum) or equivalent (M. tuberculosis)
values to already-known naphthofuroquinone compounds. Among the two
naphtho-enaminodione quinones, 28 exhibited a moderate
activity against P. falciparum with
a good selectivity index (SI > 36) while also a very high potency
against L. donovani (IC50 = 3.5 μM and SI > 28), rendering it very competitive to
the
reference drug miltefosine. All compounds were studied through molecular
modeling on their potential targets for P. falciparum, Pfbc1, and PfDHODH, where 17 showed the most favorable
interactions.
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