2-Aminoquinazolin-4(3H)-one based plasmepsin inhibitors with improved hydrophilicity and selectivity

Rasiņa, Dace; Stakanovs, Georgijs; Borysov, Oleksandr V.; Pantelejevs, Teodors; Bobrovs, Raitis; Kanepe, I.; Tars, K.; Jaudzems, Kristaps; Jirgensons, Aigars

doi:10.1016/j.bmc.2018.04.012

Cited by 13 publications

(14 citation statements)

References 41 publications

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“…It is important to note that despite more than two decades of research on plasmepsin inhibitor discovery, only a few compounds (including inhibitors 1a-c ) exhibiting parasite growth inhibition at low nanomolar concentration have been identified [11,12]. This is likely attributable to the fact that most of the efforts so far have been devoted to inhibiting plasmepsin subtypes involved in hemoglobin digestion (Plms I-IV) [[13], [14], [15], [16], [17], [18], [19], [20], [21], [22]]. Gene disruption studies have revealed that none of these hemoglobinase Plms are essential in the parasite asexual blood stage lifecycle, indicating a high degree of redundancy in the hemoglobin catabolic pathway [[23], [24], [25]].…”

Section: Introductionmentioning

confidence: 99%

Peptidomimetic plasmepsin inhibitors with potent anti-malarial activity and selectivity against cathepsin D

Zogota

Kinena

Withers‐Martinez

et al. 2019

European Journal of Medicinal Chemistry

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Following up the open initiative of anti-malarial drug discovery, a GlaxoSmithKline (GSK) phenotypic screening hit was developed to generate hydroxyethylamine based plasmepsin (Plm) inhibitors exhibiting growth inhibition of the malaria parasite Plasmodium falciparum at nanomolar concentrations. Lead optimization studies were performed with the aim of improving Plm inhibition selectivity versus the related human aspartic protease cathepsin D (Cat D). Optimization studies were performed using Plm IV as a readily accessible model protein, the inhibition of which correlates with anti-malarial activity. Guided by sequence alignment of Plms and Cat D, selectivity-inducing structural motifs were modified in the S3 and S4 sub-pocket occupying substituents of the hydroxyethylamine inhibitors. This resulted in potent anti-malarials with an up to 50-fold Plm IV/Cat D selectivity factor. More detailed investigation of the mechanism of action of the selected compounds revealed that they inhibit maturation of the P. falciparum subtilisin-like protease SUB1, and also inhibit parasite egress from erythrocytes. Our results indicate that the anti-malarial activity of the compounds is linked to inhibition of the SUB1 maturase plasmepsin subtype Plm X.

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Section: Introductionmentioning

confidence: 99%

Peptidomimetic plasmepsin inhibitors with potent anti-malarial activity and selectivity against cathepsin D

Zogota

Kinena

Withers‐Martinez

et al. 2019

European Journal of Medicinal Chemistry

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“…The synthesis of compounds 1, 2, 10, 11, 16 and 21 has been previously described [65,67] . Compounds 3-9, 12-15 and 17-20 were synthesized as shown in Scheme 1.…”

Section: Chemistrymentioning

confidence: 99%

“…By examining known non-peptidomimetic plm inhibitors, we previously hypothesized [16] , that one of the key features enabling the ligand binding to the enzyme in open flap conformation might be hydrophobic substituent capable of aromatic interactions with Trp41, Tyr77 and/or Phe111 (plm II numbering) under the flap loop. To test this hypothesis, we designed and synthesized a series of 2-aminoquinazolin-4(3H)-one based [65][66][67] inhibitors (see Figure 2) with hydrophobic substituents bearing benzene group at various locations, determined their activity against plm II, IV, V and cat D, and explored their binding pathway using funnel metadynamics simulations. This showed that the inhibitor binding mode can be estimated using metadynamics simulations, and information obtained can be used in selective inhibitor design.…”

Section: Introductionmentioning

confidence: 99%

Exploring aspartic protease inhibitor binding to design selective antimalarials

Bobrovs

Basens

Drunka

et al. 2022

Preprint

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Selectivity is a major issue in the development of drugs targeting pathogen aspartic proteases. Here we explore the selectivity determining factors by studying specifically designed malaria aspartic protease (plasmepsin) open-flap inhibitors. Metadynamics simulations are used to uncover the complex binding/unbinding pathways of these inhibitors, and describe the critical transition states in atomistic resolution. The simulation results are compared to experimentally determined enzymatic activities. Our findings demonstrate that plasmepsin inhibitor selectivity can be achieved by targeting the flap loop with hydrophobic substituents that enable ligand binding under the flap loop, as such behaviour is not observed for several other aspartic proteases. The ability to estimate compound selectivity before they are synthesized is of great importance in drug design, therefore, we expect that our approach will be useful in selective inhibitor design not only against aspartic proteases, but other enzyme classes as well.

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“…Many other authors have reported nonpeptidomimetic PM inhibitors such as those containing tetrahydroazepinmethylnaphthoate ( 68 ), phenylnaphthalene ( 69 ), dihydroquinazolinone ( 70 ), pyrrolidine ( 71 ), diazabicyclononenyloxopentanoate ( 72 ), acridine ( 73 ), diphenylhydrazine ( 74 ), and hydrazide ( 75 ) (Figure ) scaffolds. − …”

Section: Plasmodium Plasmepsin Inhibitorsmentioning

confidence: 99%

“…In fact, some studies appeared to have ignored in vitro parasite-based evaluation altogether. The lack of translatability between biochemical and whole-cell parasite activity could be ascribed, in part, to the fact that such efforts have largely focused on inhibiting PM subtypes involved in Hb degradation such as PMs I–IV (particularly I and II). ,,,,− These hemoglobinases have been shown to be nonessential at the asexual blood stage of the parasite life cycle as revealed by gene disruption studies, which is an indication of a high degree of redundancy in the hemoglobin degradation pathway. − Indeed, studies on PM knockout mutants of Plasmodium have shown that the parasite produces redundant proteolytic enzymes to make sure amino acids are supplied adequately . To be effective, a protease inhibitor should be able to hit multiple proteolytic enzymes.…”

Section: Summary and Future Perspectivementioning

confidence: 99%

Plasmepsin Inhibitors in Antimalarial Drug Discovery: Medicinal Chemistry and Target Validation (2000 to Present)

et al. 2020

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Plasmepsins represent novel antimalarial drug targets. However, plasmepsin-based antimalarial drug discovery efforts in the past 2 decades have generally suffered some drawbacks including lack of translatability of target inhibition to potent parasite inhibition in vitro and in vivo as well as poor selectivity over the related human aspartic proteases. Most studies reported in this period have over-relied on the use of hemoglobinase plasmepsins I−IV (particularly I and II) as targets for the new inhibitors even though these are known to be nonessential at the asexual stage of parasite development. Therefore, future antimalarial drug discovery efforts seeking to identify plasmepsin inhibitors should focus on incorporating nonhemoglobinase plasmepsins such as V, IX, and X in their screening in order to maximize chances of success. Additionally, there is need to go beyond just target enzymatic activity profiling to establishing cellular activity, physicochemical as well as drug metabolism and pharmacokinetics properties and finally in vivo proof-of-concept while ensuring selectivity over related human host proteases.

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2-Aminoquinazolin-4(3H)-one based plasmepsin inhibitors with improved hydrophilicity and selectivity

Cited by 13 publications

References 41 publications

Peptidomimetic plasmepsin inhibitors with potent anti-malarial activity and selectivity against cathepsin D

Peptidomimetic plasmepsin inhibitors with potent anti-malarial activity and selectivity against cathepsin D

Exploring aspartic protease inhibitor binding to design selective antimalarials

Plasmepsin Inhibitors in Antimalarial Drug Discovery: Medicinal Chemistry and Target Validation (2000 to Present)

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