Nifuroxazide and 4-Hydroxybenzhydrazone Derivatives as New Antiparasitic (Trypanosoma cruzi and Leishmania mexicana) and Anti-Mycobacterium tuberculosis Agents
<b>Background/Objectives:</b> Nifuroxazide (Nfz) is a drug that has been used as a scaffold for designing antimicrobial and antiparasitic agents. This study aimed to synthesize and evaluate in vitro of Nfz and twenty-five 4-hydroxybenzhydrazone derivatives as potential anti-<i>Trypanosoma cruzi</i>, anti-<i>Leishmania mexicana</i>, and anti-<i>Mycobacterium tuberculosis</i> agents. <b>Methods:</b> The compounds were synthesized by condensing 4-hydroxybenzhydrazide with appropriate aldehydes in acidic conditions and structurally confirmed by spectroscopic techniques. All compounds were evaluated in vitro against <i>T. cruzi</i> strains (NINOA and A1), <i>L. mexicana</i> (M379 and FCQEPS strains), and <i>M. tuberculosis</i> (H37Rv strain), followed by enzymatic assays against <i>T. cruzi</i> cysteine proteases. <b>Results:</b> Compound <b>Nfz-24</b> (IC<sub>50</sub> = 6.8 μM) had better trypanocidal activity than the reference drugs benznidazole (IC<sub>50</sub> > 30 μM) and nifurtimox (IC<sub>50</sub> > 7 μM) against the NINOA strain, and <b>Nfz-8</b> (IC<sub>50</sub> = 7.2 μM) was the compound most active against the A1 strain with a high inhibition of <i>T. cruzi</i> cysteine proteases (IC<sub>50</sub> = 4.6 μM) and low cytotoxic effects (CC<sub>50</sub> >100 μM). On the other hand, compound <b>Nfz-5</b> (IC<sub>50</sub> = 5.2 μM) had a 25-fold better leishmanicidal effect than glucantime (IC<sub>50</sub> > 125 μM) against the <i>L. mexicana</i> M379 strain, and compound <b>Nfz-13</b> had the best leishmanicidal effects (IC<sub>50</sub> = 10.2 μM) against the FCQEPS strain. Finally, <b>Nfz</b>, <b>Nfz-1</b>, and <b>Nfz-2</b> had minimum inhibitory concentration (MIC) values of 12.3, 5.1, and 18.8 μg/mL against <i>M. tuberculosis</i>, respectively. <b>Conclusions:</b> In summary, these results suggest that the compounds <b>Nfz-1</b>, <b>Nfz-2</b>, <b>Nfz-5</b>, <b>Nfz-8</b>, <b>Nfz-10</b>, <b>Nfz-15</b>, <b>Nfz-24</b>, and <b>Nfz-25</b> are candidates for further studies to develop new and more potent anti-<i>T. cruzi</i>, anti-leishmaniasis, and anti-<i>M. tuberculosis</i> agents.
Authors
- Diana V. Navarrete-Carriola (ORCID: https://orcid.org/0000-0001-8322-6731)
- Alma D. Paz-González (ORCID: https://orcid.org/0000-0002-0938-6304)
- Gildardo Rivera (ORCID: https://orcid.org/0000-0001-9842-4167)
- Charmina Aguirre-Alvarado (ORCID: https://orcid.org/0000-0003-1495-0245)
- Debasish Bandyopadhyay (ORCID: https://orcid.org/0000-0002-2726-5127)
- Verónica Alcántara‐Farfán (ORCID: https://orcid.org/0000-0002-5456-3920)
- Scott G. Franzblau (ORCID: https://orcid.org/0000-0002-8698-0243)
- Timoteo Delgado‐Maldonado (ORCID: https://orcid.org/0000-0001-8915-7351)
- Lenci K. Vázquez‐Jiménez (ORCID: https://orcid.org/0000-0002-9327-9658)
- Joaquin Cordero‐Martínez (ORCID: https://orcid.org/0000-0002-1302-6790)
- Lorena Rodrı́guez-Páez (ORCID: https://orcid.org/0000-0002-5706-8378)
- Adriana Moreno‐Rodríguez (ORCID: https://orcid.org/0000-0003-4100-8255)
- Baojie Wan
- Othman Mueen Mohammed
Institutions
- University of Al Maarif (IQ)
- The University of Texas Rio Grande Valley (US)
- University of Illinois Chicago (US)
- Instituto Politécnico Nacional (MX)
- Benito Juárez Autonomous University of Oaxaca (MX)
Publication Details
- Journal
- Pharmaceutics
- Published
- 2025-05-07
- DOI
- https://doi.org/10.3390/pharmaceutics17050621
- Citations
- 2
- Primary Topic
- Research on Leishmaniasis Studies
- Type
- article
- Field-Weighted Citation Impact
- 3.76
Funders
- Instituto Politécnico Nacional
- Comisión de Operación y Fomento de Actividades Académicas, Instituto Politécnico Nacional