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Pharmaceutics
Volume 18
Issue 6
10.3390/pharmaceutics18060664
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Article

Cross-Species Hepatic Metabolism of the Antileishmanial Chalcone NAT22 Generates Metabolites with Predicted Enhanced Affinity for the Parasite Target cTXNPx

by
Arielly R. R. Barreto
1,
Ana Paula C. Valente
2,
Edgar Schaeffer
3,
Vitor M. de Almeida
3,
Michelle F. Muzitano
4,
Thiago Barth
4,
Alessandra M. T. de Souza
5,
Bárbara de A. A. Vieira
5,
Alcides Monteiro da Silva
3,
Osvaldo A. Santos-, Filho
3,
Patrick G. Steel
6 and
Bartira Rossi-Bergmann
1,*
1
Instituto de Biofísica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, Rio de Janeiro 21941-902, RJ, Brazil
2
Instituto de Bioquímica Médica, Universidade Federal do Rio de Janeiro, Rio de Janeiro 21941-902, RJ, Brazil
3
Instituto de Pesquisas de Produtos Naturais Walter Mors, Universidade Federal do Rio de Janeiro, Rio de Janeiro 21941-902, RJ, Brazil
4
Faculdade de Farmácia, Campus Macaé, Universidade Federal do Rio de Janeiro, Macaé 27930-560, RJ, Brazil
5
Faculdade de Farmácia, Universidade Federal do Rio de Janeiro, Rio de Janeiro 21941-902, RJ, Brazil
6
Department of Chemistry, Durham University, Durham DH1 3LE, UK
*
Author to whom correspondence should be addressed.
Pharmaceutics 2026, 18(6), 664; https://doi.org/10.3390/pharmaceutics18060664 (registering DOI)
Submission received: 1 March 2026 / Revised: 5 May 2026 / Accepted: 8 May 2026 / Published: 27 May 2026
(This article belongs to the Section Biopharmaceutics)
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Abstract

Background/Objectives: Human and canine leishmaniases are neglected diseases with limited therapeutic options. The nitrochalcone NAT22, a high-affinity inhibitor of the essential parasite enzyme tryparedoxin peroxidase (cTXNPx), has emerged as a promising antileishmanial candidate. Interestingly, NAT22 demonstrated superior efficacy when administered orally rather than intralesionally, suggesting a metabolism-driven activity enhancement. Since in vivo studies with chalcones have been conducted exclusively in mice, this study aimed to determine whether mice are suitable models for oral chalcone therapies for human and canine leishmaniases and to identify metabolites with potential antileishmanial activity. Methods: NAT22 hepatic metabolism was investigated using in silico prediction and in vitro liver microsomal assays from rats, mice, humans, and dogs. Metabolites were identified by LC-MS/MS and NMR, and docking studies were performed against cTXNPx. Results: In silico analysis predicted metabolism mainly by CYP1A2, CYP2A6, CYP2C8, and CYP3A4. Seven metabolites (M1–M7) were identified by LC-MS/MS and NMR in all species except mice, whose microsomes did not generate M6. Structural analyses indicated preservation of the α,β-enone system and nitro-substituted B ring in all metabolites. Docking studies showed that metabolites M2 and M4 displayed stronger predicted binding energies than NAT22. Conclusions: NAT22 undergoes hepatic phase I metabolism generating two metabolites with enhanced predicted interaction with cTXNPx. The similarity between human and canine metabolic profiles supports the translational relevance of oral NAT22 therapy in leishmaniasis, while metabolites M2 and M4 emerge as candidates for validation in local treatment of cutaneous leishmaniasis.
Keywords: chalcone; liver microsomes; CYP; cTXNPx; leishmaniasis chalcone; liver microsomes; CYP; cTXNPx; leishmaniasis
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MDPI and ACS Style

Barreto, A.R.R.; Valente, A.P.C.; Schaeffer, E.; de Almeida, V.M.; Muzitano, M.F.; Barth, T.; Souza, A.M.T.d.; Vieira, B.d.A.A.; da Silva, A.M.; Santos-, O.A., Filho; et al. Cross-Species Hepatic Metabolism of the Antileishmanial Chalcone NAT22 Generates Metabolites with Predicted Enhanced Affinity for the Parasite Target cTXNPx. Pharmaceutics 2026, 18, 664. https://doi.org/10.3390/pharmaceutics18060664

AMA Style

Barreto ARR, Valente APC, Schaeffer E, de Almeida VM, Muzitano MF, Barth T, Souza AMTd, Vieira BdAA, da Silva AM, Santos- OA Filho, et al. Cross-Species Hepatic Metabolism of the Antileishmanial Chalcone NAT22 Generates Metabolites with Predicted Enhanced Affinity for the Parasite Target cTXNPx. Pharmaceutics. 2026; 18(6):664. https://doi.org/10.3390/pharmaceutics18060664

Chicago/Turabian Style

Barreto, Arielly R. R., Ana Paula C. Valente, Edgar Schaeffer, Vitor M. de Almeida, Michelle F. Muzitano, Thiago Barth, Alessandra M. T. de Souza, Bárbara de A. A. Vieira, Alcides Monteiro da Silva, Osvaldo A. Santos-, Filho, and et al. 2026. "Cross-Species Hepatic Metabolism of the Antileishmanial Chalcone NAT22 Generates Metabolites with Predicted Enhanced Affinity for the Parasite Target cTXNPx" Pharmaceutics 18, no. 6: 664. https://doi.org/10.3390/pharmaceutics18060664

APA Style

Barreto, A. R. R., Valente, A. P. C., Schaeffer, E., de Almeida, V. M., Muzitano, M. F., Barth, T., Souza, A. M. T. d., Vieira, B. d. A. A., da Silva, A. M., Santos-, O. A., Filho, Steel, P. G., & Rossi-Bergmann, B. (2026). Cross-Species Hepatic Metabolism of the Antileishmanial Chalcone NAT22 Generates Metabolites with Predicted Enhanced Affinity for the Parasite Target cTXNPx. Pharmaceutics, 18(6), 664. https://doi.org/10.3390/pharmaceutics18060664

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