New Amino Naphthoquinone Derivatives as Anti-<i>Trypanosoma cruzi</i> Agents Targeting Trypanothione Reductase
To develop novel chemotherapeutic alternatives for the treatment of Chagas disease, in this study, a set of new amino naphthoquinone derivatives were synthesised and evaluated in vitro on the epimastigote and trypomastigote forms of <i>Trypanosoma cruzi</i> strains (NINOA and INC-5) and...
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| Main Authors: | , , , , , , , , , |
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| Format: | Book |
| Published: |
MDPI AG,
2022-05-01T00:00:00Z.
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| Summary: | To develop novel chemotherapeutic alternatives for the treatment of Chagas disease, in this study, a set of new amino naphthoquinone derivatives were synthesised and evaluated in vitro on the epimastigote and trypomastigote forms of <i>Trypanosoma cruzi</i> strains (NINOA and INC-5) and on J774 murine macrophages. The design of the new naphthoquinone derivatives considered the incorporation of nitrogenous fragments with different substitution patterns present in compounds with activity on <i>T. cruzi,</i> and, thus, 19 compounds were synthesised in a simple manner. Compounds <b>2e</b> and <b>7j</b> showed the lowest IC<sub>50</sub> values (0.43 µM against both strains for <b>2e</b> and 0.19 µM and 0.92 µM for <b>7j</b>). Likewise, <b>7j</b> was more potent than the reference drug, benznidazole, and was more selective on epimastigotes. To postulate a possible mechanism of action, molecular docking studies were performed on <i>T. cruzi</i> trypanothione reductase (<i>Tc</i>TR), specifically at a site in the dimer interface, which is a binding site for this type of naphthoquinone. Interestingly, <b>7j</b> was one of the compounds that showed the best interaction profile on the enzyme; therefore, <b>7j</b> was evaluated on TR, which behaved as a non-competitive inhibitor. Finally, <b>7j</b> was predicted to have a good pharmacokinetic profile for oral administration. Thus, the naphthoquinone nucleus should be considered in the search for new trypanocidal agents based on our hit <b>7j</b>. |
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| Item Description: | 10.3390/pharmaceutics14061121 1999-4923 |