Benzimidazole Derivatives as New and Selective Inhibitors of Arginase from Leishmania mexicana with Biological Activity against Promastigotes and Amastigotes
Abstract
:1. Introduction
2. Results
2.1. Virtual Screening and LmARG Inhibition
2.2. Human Arginase 1 Inhibition
2.3. Molecular Dynamics
2.4. LmARG-Inhibitor Interactions
2.5. Biological Activity Evaluation and Cytotoxicity
2.6. In Silico Physichemical and ADME-Tox Predictions
3. Discussion
4. Materials and Methods
4.1. Virtual Screening
4.2. Cloning of L. mexicana Arginase Gene
4.3. Cloning of Human Arginase 1 Gene
4.4. Expression and Purification of Arginases
4.5. Enzyme Activity
4.6. Inhibition Assays
4.7. Molecular Dynamics
4.8. In Silico ADME-Tox Prediction
4.9. Biological Activity against Leishmania mexicana Promastigotes
4.10. Biological Activity against Leishmania mexicana Amastigotes
4.11. Cytotoxicity Assays
4.12. Synthesis of Benzimidazole Derivatives
4.13. Statistical Analysis
5. Conclusions
Supplementary Materials
Author Contributions
Funding
Acknowledgments
Conflicts of Interest
References
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Compound | Chemical Structure | Docking Score (kcal/mol) | % Inhibition LmARG [200 μM] |
---|---|---|---|
1 | −5.46 | 100% | |
2 | −5.04 | 100% | |
3 | −6.39 | 60% | |
4 | −6.05 | 56% | |
5 | −5.96 | 56% | |
6 | −8.38 | 46% | |
7 | −6.05 | 40% | |
8 | −6.00 | 40% | |
9 | −5.04 | 36% | |
10 | −6.65 | 33% |
Compound | IC50 (µM) | CC50 (µM) | SI 1 | ||
---|---|---|---|---|---|
Promastigotes | Amastigotes | Promastigotes | Amastigotes | ||
1 | 64 | 32 | >417 2 | 6.5 | 13 |
2 | 132 | 101 | >414 2 | 3.1 | 4.1 |
Glucantime | 101 | 35 | >273 3 | 2.7 | 7.8 |
Amphotericin B | 0.89 | 1.3 | 7.4 3 | 8.3 | 6.2 |
Miltefosine | 8.1 | 8.6 | 141 3 | 17.4 | 2 |
Descriptor | Compound 1 | Compound 2 |
---|---|---|
MW 1 | 239.66 | 241.7 |
logP 1 | 2.35 | 2.1 |
logD 1 | 2.63 | 2.03 |
logSw 1 | −2.93 | −2.82 |
tPSA 1 | 56.15 | 97.07 |
RB 1 | 2 | 2 |
HBD 1 | 1 | 3 |
HBA 1 | 5 | 4 |
Lipinski’s violations 1 | none | none |
Veber Rules 1 | Good | Good |
Egan Rules 1 | Good | Good |
BBB+ 2 | 0.9584 | 0.9117 |
HIA+ 2 | 0.9965 | 0.9819 |
Caco2 2 | 0.6531 | 0.5468 |
Lysosome 2 | 0.6217 | 0.6217 |
Predicted LD50 3 | 5050 mg/kg | 705 mg/kg |
Predicted toxicity class 3 | 6 | 4 |
Toxicity targets 3 | no binding | no binding |
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Betancourt-Conde, I.; Avitia-Domínguez, C.; Hernández-Campos, A.; Castillo, R.; Yépez-Mulia, L.; Oria-Hernández, J.; Méndez, S.T.; Sierra-Campos, E.; Valdez-Solana, M.; Martínez-Caballero, S.; et al. Benzimidazole Derivatives as New and Selective Inhibitors of Arginase from Leishmania mexicana with Biological Activity against Promastigotes and Amastigotes. Int. J. Mol. Sci. 2021, 22, 13613. https://doi.org/10.3390/ijms222413613
Betancourt-Conde I, Avitia-Domínguez C, Hernández-Campos A, Castillo R, Yépez-Mulia L, Oria-Hernández J, Méndez ST, Sierra-Campos E, Valdez-Solana M, Martínez-Caballero S, et al. Benzimidazole Derivatives as New and Selective Inhibitors of Arginase from Leishmania mexicana with Biological Activity against Promastigotes and Amastigotes. International Journal of Molecular Sciences. 2021; 22(24):13613. https://doi.org/10.3390/ijms222413613
Chicago/Turabian StyleBetancourt-Conde, Irene, Claudia Avitia-Domínguez, Alicia Hernández-Campos, Rafael Castillo, Lilián Yépez-Mulia, Jesús Oria-Hernández, Sara T. Méndez, Erick Sierra-Campos, Mónica Valdez-Solana, Siseth Martínez-Caballero, and et al. 2021. "Benzimidazole Derivatives as New and Selective Inhibitors of Arginase from Leishmania mexicana with Biological Activity against Promastigotes and Amastigotes" International Journal of Molecular Sciences 22, no. 24: 13613. https://doi.org/10.3390/ijms222413613