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Background <p>The discovery of novel antimalarial drugs against <i>Plasmodium falciparum</i> has become globally urgent due to the consistent increase in mortality, morbidity, and drug resistance in endemic areas.</p> Methods <p>Using an in-house library, novel antimalarial agents were identified through in vitro high-throughput screening (HTS) and meta-analysis. Hit compounds were selected from the primary HTS at 10 µM and confirmed in a dose-dependent manner to determine their IC₅₀ values. The identified hit molecules were further selected based on the following criteria: novelty, antimalarial activity (IC<sub>50</sub>), pharmacokinetic properties (C<sub>max</sub> and T<sub>1/2</sub>), mechanism of action, and safety (in vitro and in vivo) (CC<sub>50</sub>, SI, LD<sub>50</sub>, and MTD). In vitro and in vivo antimalarial activity against drug-sensitive and resistant strains (3D7, NF54 and K1, Dd2, Dd2-R539T (+), and CamWT-C580Y (+)) and the rodent <i>Plasmodium berghei</i> parasite-infected animal model, respectively, were subsequently used to validate hit compounds.</p> Results <p>Based on the top 3% threshold, 256 compounds were selected for dose‒response curve analysis from the HTS. Among them, 110 compounds without published research related to <i>Plasmodium</i> and 157 compounds with IC<sub>50</sub> values &lt; 1 µM were identified. Further analysis confirmed 69 compounds with median lethal doses, maximum tolerated doses or treated doses greater than 20 mg/kg, 48 compounds with FDA approval, 29 compounds characterized by C<sub>max</sub> &gt; IC<sub>100</sub> and T<sub>1/2</sub> &gt; 6 h, and 38 compounds with a potential mechanism in <i>Plasmodium</i>. Next, 19 candidates were further evaluated for in vitro inhibition of drug-resistant parasites and inhibition in a mouse model of <i>P. berghei</i> parasites<i>.</i> Notably, three potent inhibitors were identified, exhibiting 95.9% and 81.4% suppression via oral delivery at a dose of 50 mg/kg ONX-0914 and methotrexate, respectively, and 96.4% suppression via intraperitoneal delivery at a dose of 20 mg/kg of an antimony compound. In addition, strong in vitro antimalarial activity was demonstrated against CQ- and ART-sensitive and resistant strains (IC<sub>50</sub> &lt; 500 nM).</p> Conclusions <p>Combining HTS and meta-analysis provides a robust method for screening antimalarial candidate compounds and identifying new hits with in vivo activity as candidates to treat drug-resistant malarial strains.</p>

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High-throughput screening and meta-analysis for lead compounds in antimalarial drug discovery

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年11月6日

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  • Nguyen Van Truong,
  • Seok-Won Na,
  • Ji Hoon Park,
  • Tuyet-Kha Nguyen,
  • Nguyen Sy Thau,
  • Thi-Thanh Hang Chu,
  • Bazgha Sanaullah,
  • Ch Venkataramaiah,
  • Jin-Hee Han,
  • Sung-Hun Na,
  • Won-Sun Park,
  • Wan-Joo Chun,
  • Joo Hwan No,
  • Eun-Taek Han

摘要

Background

The discovery of novel antimalarial drugs against Plasmodium falciparum has become globally urgent due to the consistent increase in mortality, morbidity, and drug resistance in endemic areas.

Methods

Using an in-house library, novel antimalarial agents were identified through in vitro high-throughput screening (HTS) and meta-analysis. Hit compounds were selected from the primary HTS at 10 µM and confirmed in a dose-dependent manner to determine their IC₅₀ values. The identified hit molecules were further selected based on the following criteria: novelty, antimalarial activity (IC50), pharmacokinetic properties (Cmax and T1/2), mechanism of action, and safety (in vitro and in vivo) (CC50, SI, LD50, and MTD). In vitro and in vivo antimalarial activity against drug-sensitive and resistant strains (3D7, NF54 and K1, Dd2, Dd2-R539T (+), and CamWT-C580Y (+)) and the rodent Plasmodium berghei parasite-infected animal model, respectively, were subsequently used to validate hit compounds.

Results

Based on the top 3% threshold, 256 compounds were selected for dose‒response curve analysis from the HTS. Among them, 110 compounds without published research related to Plasmodium and 157 compounds with IC50 values < 1 µM were identified. Further analysis confirmed 69 compounds with median lethal doses, maximum tolerated doses or treated doses greater than 20 mg/kg, 48 compounds with FDA approval, 29 compounds characterized by Cmax > IC100 and T1/2 > 6 h, and 38 compounds with a potential mechanism in Plasmodium. Next, 19 candidates were further evaluated for in vitro inhibition of drug-resistant parasites and inhibition in a mouse model of P. berghei parasites. Notably, three potent inhibitors were identified, exhibiting 95.9% and 81.4% suppression via oral delivery at a dose of 50 mg/kg ONX-0914 and methotrexate, respectively, and 96.4% suppression via intraperitoneal delivery at a dose of 20 mg/kg of an antimony compound. In addition, strong in vitro antimalarial activity was demonstrated against CQ- and ART-sensitive and resistant strains (IC50 < 500 nM).

Conclusions

Combining HTS and meta-analysis provides a robust method for screening antimalarial candidate compounds and identifying new hits with in vivo activity as candidates to treat drug-resistant malarial strains.