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Background <p>Visceral leishmaniasis (VL) remains a fatal parasitic disease with limited treatment options and growing drug resistance. To address this challenge, we synthesized and characterized HYBRID2, an imidazoquinoline-based TLR7/8 agonist and explored its untapped potential against <i>Leishmania</i> through in vitro and in silico studies.</p> Results <p>HYBRID2 effectively eliminated both promastigote and intracellular amastigote forms of <i>Leishmania donovani</i> (Promastigote IC<sub>50</sub>: 6.50 ± 2.20&#xa0;µM; Amastigote IC<sub>50</sub>: 7.56 ± 1.58&#xa0;µM), while exhibiting moderate cytotoxicity (Raw macrophages CC<sub>50</sub>: 42.30 ± 3.88&#xa0;µM; HeLa CC<sub>50</sub>: 36.66 ± 4.37&#xa0;µM). The mechanistic investigation confirmed that HYBRID2 induced a marked arrest of the parasite cell cycle in the sub-G<sub>0</sub>/G<sub>1</sub> population (84.64% <i>vs.</i> 7.23% in untreated; <i>p</i> &lt; 0.0001), significantly inhibited parasite growth, and robustly enhanced Reactive Oxygen Species (ROS) (607.66 mean fluorescence intensity; <i>p</i> &lt; 0.0001) and Nitric Oxide (NO) production (22.53 ± 0.73&#xa0;µM; <i>p</i> &lt; 0.0001), indicating a strong immunomodulatory role associated through its dual TLR7/8 agonist activity. Interestingly, the in silico studies and ADMET analyses of HYBRID2 suggested strong multi-target interactions, with the strongest affinity observed for anti-leishmanial drug target trypanothione reductase, alongside favorable pharmacokinetic properties.</p> Conclusions <p>This study highlights an innovative and disease-relevant application of a dual TLR7/8 agonist with a distinct immunopharmacological profile, reinforced by strong in silico target engagement, underscoring its potential for host-directed therapeutic development against visceral leishmaniasis.</p> Graphical abstract <p></p>

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TLR7/8 agonist HYBRID2 as a dual-action compound against Leishmania donovani: antiparasitic and immunomodulatory effects

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年5月11日

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  • Sandeep Kaur,
  • Kushvinder Kumar,
  • Shivani Thakur,
  • Deepak B. Salunke,
  • Sukhbir Kaur

摘要

Background

Visceral leishmaniasis (VL) remains a fatal parasitic disease with limited treatment options and growing drug resistance. To address this challenge, we synthesized and characterized HYBRID2, an imidazoquinoline-based TLR7/8 agonist and explored its untapped potential against Leishmania through in vitro and in silico studies.

Results

HYBRID2 effectively eliminated both promastigote and intracellular amastigote forms of Leishmania donovani (Promastigote IC50: 6.50 ± 2.20 µM; Amastigote IC50: 7.56 ± 1.58 µM), while exhibiting moderate cytotoxicity (Raw macrophages CC50: 42.30 ± 3.88 µM; HeLa CC50: 36.66 ± 4.37 µM). The mechanistic investigation confirmed that HYBRID2 induced a marked arrest of the parasite cell cycle in the sub-G0/G1 population (84.64% vs. 7.23% in untreated; p < 0.0001), significantly inhibited parasite growth, and robustly enhanced Reactive Oxygen Species (ROS) (607.66 mean fluorescence intensity; p < 0.0001) and Nitric Oxide (NO) production (22.53 ± 0.73 µM; p < 0.0001), indicating a strong immunomodulatory role associated through its dual TLR7/8 agonist activity. Interestingly, the in silico studies and ADMET analyses of HYBRID2 suggested strong multi-target interactions, with the strongest affinity observed for anti-leishmanial drug target trypanothione reductase, alongside favorable pharmacokinetic properties.

Conclusions

This study highlights an innovative and disease-relevant application of a dual TLR7/8 agonist with a distinct immunopharmacological profile, reinforced by strong in silico target engagement, underscoring its potential for host-directed therapeutic development against visceral leishmaniasis.

Graphical abstract