Antimalarial Inhibitors Targeting Epigenetics or Mitochondria in Plasmodium falciparum: Recent Survey upon Synthesis and Biological Evaluation of Potential Drugs against Malaria

Abstract

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.

DNA sequence context and the chromatin landscape differentiate sequence-specific transcription factor binding in the human malaria parasite,Plasmodium falciparum

“…In this context, we found several solutions including TFs that rely on sequence context to differentiate genome-wide binding site selection and others that are coordinated through changes in chromatin state features. Our findings are also relevant from a therapeutic perspective since ApiAP2 TFs are unique to plant and eukaryotic parasite genomes and have therefore been proposed as future antiparasitic drug targets 105,[111][112][113][114][115] .…”

Design of Anti-infectious Agents from Lawsone in a Three-Component Reaction with Aldehydes and Isocyanides

“…In fact, naphthoquinone derivatives based on lawsone scaffold are known to interfere with these two mitochondrial targets of P. falciparum …”

“…In fact, naphthoquinone derivatives based on lawsone scaffold are known to interfere with these two mitochondrial targets of P. falciparum. 26 The AlphaFold2-modeled structure of the cytochrome enzyme (Q7HP03) was used to characterize the predicted interactions between the compounds described and the P. falciparum target bc1. 49 All local quality measures of the predicted protein structure were assessed as very good (Figure 6), that is, per-residue confidence scores (pLDDT) for the model were all very high near the binding site region (central groove inside the α-helices, near Tyr 263) and had low expected position error (dark green in Figure 7, in angstrom) for the predicted alignment errors (PAE), that is, the values for expected position error at residue x when the predicted and true structures are aligned on residue y.…”

“…Unfortunately, strong P. falciparum resistance against atovaquone arises rapidly in the field. In this respect, efforts to design and prepare naphthoquinones and naphthofuroquinones based on lawsone scaffold have been pursued worldwide: 26 Borgati et al 12 reported the synthesis of a series of naphthoquinones and naphthofuroquinones through functionalization of lawsone either on the 2-hydroxy group affording alkoxy derivatives or on the C-3 alkene carbon atom, followed by cyclization, thus leading to naphthofuroquinones. Among all the synthesized compounds, naphthofuroquinone 6 exhibited the lowest IC 50 value against the chloroquine-resistant P. falciparum W2 strain (Figure 2).…”

“…In this respect, efforts to design and prepare naphthoquinones and naphthofuroquinones based on lawsone scaffold have been pursued worldwide: 26 …”