Synthesis, Biological Evaluation, Molecular Dynamics, and QM-MM Calculation of Spiro-Acridine Derivatives Against Leishmaniasis
Abstract
:1. Introduction
2. Materials and Methods
2.1. Chemistry
2.1.1. Procedure for Synthesis of AMTAC Derivatives
2.1.2. Procedure for Synthesis of ACMD Derivatives
2.2. Experimental Biological Evaluation
2.2.1. Antileishmanial Activity
Parasite Culture
Determination of the Inhibitory Effect in Promastigote Forms of L. amazonensis and L. infantum Strains
Determination of the Inhibitory Effect in Amastigote Anexic Forms of L. amazonensis
2.2.2. Determination of Cell Viability
Assessment of the Hemocompatibility of Spiro-Acridine Derivatives in Red Blood Cells
Determination of the Cytotoxic Effects in J774 Macrophage Cultures
2.2.3. Assessment of Cytokine Profile in Immunological Responses
2.2.4. Evaluation of the Production of Reactive Oxygen and Nitrogen Species
2.2.5. Statistical Analysis
2.3. Computational Experiments
2.3.1. Molecular Docking Simulation
2.3.2. Molecular Dynamics Simulations
2.3.3. MM-PBSA Calculations
2.3.4. QM-MM Binding Free Energy Calculations
3. Results
3.1. Synthesis of the Compounds
3.2. Biological Evaluation
3.2.1. Anti-Promastigote Activity
3.2.2. Anti-Amastigote Evaluation
3.2.3. Cytokine Profile of Immunological Responses
3.2.4. Reactive Oxygen Species (ROS) and Reactive Nitrogen Species (RNS) Assays
3.3. Molecular Modeling Studies to Propose the Biological Target
3.3.1. Molecular Docking
3.3.2. Molecular Dynamics Simulations and MM-PBSA Calculations
3.3.3. QM-MM Calculations
4. Discussion
5. Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
Abbreviations
1H-NMR | Hydrogen Nuclear Magnetic Resonance |
13C-NMR | Carbon Nuclear Magnetic Resonance |
ASP | Astex Statistical Potential |
B.O.D. | Biochemical Oxygen Demand |
CBA | Cytometry Bead Assay |
ChemPLP | Chemical Piecewise Linear Potential |
DCCM | Dynamic Cross-Correlation Matrix |
DCF | 2′,7′-dichlorodihydrofluorescein |
DAF-FM | 4-amino-5-methylamino-2′,7′-difluorofluorescein |
DMEM | Dulbecco’s Modified Eagle Medium |
DMSO-d6 | Deuterated Dimethyl Sulfoxide |
FBS | Fetal Bovine Serum |
IR | Infrared |
MALDI-TOF | Matrix-assisted Laser Desorption/-Time-of-flight |
MS | Mass Spectrometry |
MM-PBSA | Molecular Mechanics Poisson–Boltzmann Surface Area |
M.W. | Molecular Weight |
MTT | [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide] |
NNN | Novy–MacNeal–Nicolle |
NTD | Neglected Tropical Disease |
PBS | Phosphate-buffered Saline |
PCA | Principal Component Analysis |
QM-MM | Quantum Mechanics-Molecular Mechanics |
RMSD | Root-mean-square Deviation |
Rg | Radius of gyration |
SASA | Solvent-accessible Surface Area |
TLC | Thin Layer Chromatography |
References
- Elmahallawy, E.K.; Sampedro Martínez, A.; Rodriguez-Granger, J.; Hoyos-Mallecot, Y.; Agil, A.; Navarro Mari, J.M.; Gutierrez Fernández, J. Diagnosis of Leishmaniasis. J. Infect. Dev. Ctries. 2014, 8, 961–972. [Google Scholar] [CrossRef] [PubMed]
- Santiago, A.S.; Pita, S.S.d.R.; Guimarães, E.T. Tratamento Da Leishmaniose, Limitações Da Terapêutica Atual e a Necessidade de Novas Alternativas: Uma Revisão Narrativa. Res. Soc. Dev. 2021, 10, e29510716543. [Google Scholar] [CrossRef]
- WHO. Leishmaniasis. Available online: https://www.who.int/news-room/fact-sheets/detail/leishmaniasis (accessed on 26 September 2023).
- Nascimento, I.J.d.S.; Cavalcanti, M.d.A.T.; de Moura, R.O. Exploring N-Myristoyltransferase as a Promising Drug Target against Parasitic Neglected Tropical Diseases. Eur. J. Med. Chem. 2023, 258, 115550. [Google Scholar] [CrossRef]
- Saini, I.; Joshi, J.; Kaur, S. Unwelcome Prevalence of Leishmaniasis with Several Other Infectious Diseases. Int. Immunopharmacol. 2022, 110, 109059. [Google Scholar] [CrossRef]
- Elmahallawy, E.K.; Alkhaldi, A.A.M.; Saleh, A.A. Host Immune Response against Leishmaniasis and Parasite Persistence Strategies: A Review and Assessment of Recent Research. Biomed. Pharmacother. 2021, 139, 111671. [Google Scholar] [CrossRef] [PubMed]
- Anversa, L.S.; Tiburcio, M.G.S.; Richini-Pereira, V.N.B.; Ramirez, L.E. Human Leishmaniasis in Brazil: A General Review. Rev. Assoc. Med. Bras. 2018, 64, 281–289. [Google Scholar] [CrossRef]
- Upadhyay, A.; Kushwaha, P.; Gupta, S.; Dodda, R.P.; Ramalingam, K.; Kant, R.; Goyal, N.; Sashidhara, K.V. Synthesis and Evaluation of Novel Triazolyl Quinoline Derivatives as Potential Antileishmanial Agents. Eur. J. Med. Chem. 2018, 154, 172–181. [Google Scholar] [CrossRef]
- Ikeogu, N.M.; Akaluka, G.N.; Edechi, C.A.; Salako, E.S.; Onyilagha, C.; Barazandeh, A.F.; Uzonna, J.E. Leishmania Immunity: Advancing Immunotherapy and Vaccine Development. Microorganisms 2020, 8, 1201. [Google Scholar] [CrossRef]
- Gabriel, Á.; Valério-Bolas, A.; Palma-Marques, J.; Mourata-Gonçalves, P.; Ruas, P.; Dias-Guerreiro, T.; Santos-Gomes, G. Cutaneous Leishmaniasis: The Complexity of Host’s Effective Immune Response against a Polymorphic Parasitic Disease. J. Immunol. Res. 2019, 2019, 2603730. [Google Scholar] [CrossRef]
- Tiwari, N.; Gedda, M.R.; Tiwari, V.K.; Singh, S.P.; Singh, R.K. Limitations of Current Therapeutic Options, Possible Drug Targets and Scope of Natural Products in Control of Leishmaniasis. Mini-Rev. Med. Chem. 2017, 18, 26–41. [Google Scholar] [CrossRef]
- Molkara, S.; Reza Taheri, A.; Sabouri Rad, S. Systemic Treatments of Leishmaniasis: A Narrative Review. Rev. Clin. Med. 2019, 6, 91. [Google Scholar]
- de Araújo-Vilges, K.M.; de Oliveira, S.V.; Couto, S.C.P.; Fokoue, H.H.; Romero, G.A.S.; Kato, M.J.; Romeiro, L.A.S.; Leite, J.R.S.A.; Kuckelhaus, S.A.S. Effect of Piplartine and Cinnamides on Leishmania Amazonensis, Plasmodium Falciparum and on Peritoneal Cells of Swiss Mice. Pharm. Biol. 2017, 55, 1601–1607. [Google Scholar] [CrossRef] [PubMed]
- Frézard, F.; Demicheli, C.; Ribeiro, R.R. Pentavalent Antimonials: New Perspectives for Old Drugs. Molecules 2009, 14, 2317–2336. [Google Scholar] [CrossRef]
- Nascimento, I.J.d.S.; de Aquino, T.M.; da Silva-Júnior, E.F. The New Era of Drug Discovery: The Power of Computer-Aided Drug Design (CADD). Lett. Drug Des. Discov. 2022, 19, 951–955. [Google Scholar] [CrossRef]
- dos Santos Nascimento, I.J.; Santana Gomes, J.N.; de Oliveira Viana, J.; de Medeiros e Silva, Y.M.S.; Barbosa, E.G.; de Moura, R.O. The Power of Molecular Dynamics Simulations and Their Applications to Discover Cysteine Protease Inhibitors. Mini-Reviews Med. Chem. 2023, 23, 1125–1146. [Google Scholar] [CrossRef]
- Werbovetz, K.A.; Lehnert, E.K.; Macdonald, T.L.; Pearson, R.D. Cytotoxicity of Acridine Compounds for Leishmania Promastigotes in Vitro. Antimicrob. Agents Chemother. 1992, 36, 495–497. [Google Scholar] [CrossRef]
- Mauel, J.; Denny, W.; Gamage, S.; Ransijn, A.; Wojcik, S.; Figgitt, D.; Ralph, R. 9-Anilinoacridines as Potential Antileishmanial Agents. Antimicrob. Agents Chemother. 1993, 37, 991–996. [Google Scholar] [CrossRef]
- Gamage, S.A.; Figgitt, D.P.; Wojcik, S.J.; Ralph, R.K.; Ransijn, A.; Mauel, J.; Yardley, V.; Snowdon, D.; Croft, S.L.; Denny, W.A. Structure-Activity Relationships for the Antileishmanial and Antitrypanosomal Activities of 1′-Substituted 9-Anilinoacridines. J. Med. Chem. 1997, 40, 2634–2642. [Google Scholar] [CrossRef] [PubMed]
- Di Giorgio, C.; Delmas, F.; Filloux, N.; Robin, M.; Seferian, L.; Azas, N.; Gasquet, M.; Costa, M.; Timon-David, P.; Galy, J.P. In Vitro Activities of 7-Substituted 9-Chloro and 9-Amino-2-Methoxyacridines and Their Bis- and Tetra-Acridine Complexes against Leishmania Infantum. Antimicrob. Agents Chemother. 2003, 47, 174–180. [Google Scholar] [CrossRef]
- Girault, S.; Grellier, P.; Berecibar, A.; Maes, L.; Mouray, E.; Lemière, P.; Debreu, M.A.; Davioud-Charvet, E.; Sergheraert, C. Antimalarial, Antitrypanosomal, and Antileishmanial Activities and Cytotoxicity of Bis(9-Amino-6-Chloro-2-Methoxyacridines): Influence of the Linker. J. Med. Chem. 2000, 43, 2646–2654. [Google Scholar] [CrossRef]
- Almeida, F.S.; Sousa, G.L.S.; Rocha, J.C.; Ribeiro, F.F.; de Oliveira, M.R.; de Lima Grisi, T.C.S.; Araújo, D.A.M.; Michelangela, M.S.; Castro, R.N.; Amaral, I.P.G.; et al. In Vitro Anti-Leishmania Activity and Molecular Docking of Spiro-Acridine Compounds as Potential Multitarget Agents against Leishmania Infantum. Bioorganic Med. Chem. Lett. 2021, 49, 128289. [Google Scholar] [CrossRef] [PubMed]
- Almeida, S.M.V.d.; Lafayette, E.A.; Silva, W.L.; Lima Serafim, V.d.; Menezes, T.M.; Neves, J.L.; Ruiz, A.L.T.G.; Carvalho, J.E.d.; Moura, R.O.d.; Beltrão, E.I.C.; et al. New Spiro-Acridines: DNA Interaction, Antiproliferative Activity and Inhibition of Human DNA Topoisomerases. Int. J. Biol. Macromol. 2016, 92, 467–475. [Google Scholar] [CrossRef] [PubMed]
- Gouveia, R.G.; Ribeiro, A.G.; Segundo, M.Â.S.P.; de Oliveira, J.F.; de Lima, M.d.C.A.; de Lima Souza, T.R.C.; de Almeida, S.M.V.; de Moura, R.O. Synthesis, DNA and Protein Interactions and Human Topoisomerase Inhibition of Novel Spiroacridine Derivatives. Bioorganic Med. Chem. 2018, 26, 5911–5921. [Google Scholar] [CrossRef]
- de Lima Serafim, V.; Félix, M.B.; Frade Silva, D.K.; Rodrigues, K.A.d.F.; Andrade, P.N.; de Almeida, S.M.V.; de Albuquerque dos Santos, S.; de Oliveira, J.F.; de Lima, M.d.C.A.; Mendonça-Junior, F.J.B.; et al. New Thiophene–Acridine Compounds: Synthesis, Antileishmanial Activity, DNA Binding, Chemometric, and Molecular Docking Studies. Chem. Biol. Drug Des. 2018, 91, 1141–1155. [Google Scholar] [CrossRef]
- Albino, S.L.; da Silva Moura, W.C.; Reis, M.M.L.d.; Sousa, G.L.S.; da Silva, P.R.; de Oliveira, M.G.C.; Borges, T.K.d.S.; Albuquerque, L.F.F.; de Almeida, S.M.V.; de Lima, M. do C.A.; et al. ACW-02 an Acridine Triazolidine Derivative Presents Antileishmanial Activity Mediated by DNA Interaction and Immunomodulation. Pharmaceuticals 2023, 16, 204. [Google Scholar] [CrossRef]
- Van De Ven, H.; Paulussen, C.; Feijens, P.B.; Matheeussen, A.; Rombaut, P.; Kayaert, P.; Van Den Mooter, G.; Weyenberg, W.; Cos, P.; Maes, L.; et al. PLGA Nanoparticles and Nanosuspensions with Amphotericin B: Potent in Vitro and in Vivo Alternatives to Fungizone and AmBisome. J. Control. Release 2012, 161, 795–803. [Google Scholar] [CrossRef] [PubMed]
- Kückelhaus, S.A.S.; de Aquino, D.S.; Borges, T.K.; Moreira, D.C.; Leite, L.d.M.; Muniz-Junqueira, M.I.; Kückelhaus, C.S.; Sierra Romero, G.A.; Prates, M.V.; Bloch, C.; et al. Phylloseptin-1 Is Leishmanicidal for Amastigotes of Leishmania Amazonensis inside Infected Macrophages. Int. J. Environ. Res. Public Health 2020, 17, 4856. [Google Scholar] [CrossRef]
- Kückelhaus, S.A.S.; Leite, J.R.S.A.; Muniz-Junqueira, M.I.; Sampaio, R.N.; Bloch, C.; Tosta, C.E. Antiplasmodial and Antileishmanial Activities of Phylloseptin-1, an Antimicrobial Peptide from the Skin Secretion of Phyllomedusa azurea (Amphibia). Exp. Parasitol. 2009, 123, 11–16. [Google Scholar] [CrossRef]
- BERNSTEIN, F.C.; KOETZLE, T.F.; WILLIAMS, G.J.B.; MEYER, E.F.; BRICE, M.D.; RODGERS, J.R.; KENNARD, O.; SHIMANOUCHI, T.; TASUMI, M. The Protein Data Bank. A Computer-Based Archival File for Macromolecular Structures. Eur. J. Biochem. 1977, 80, 319–324. [Google Scholar] [CrossRef]
- Goddard, T.D.; Huang, C.C.; Ferrin, T.E. Software Extensions to UCSF Chimera for Interactive Visualization of Large Molecular Assemblies. Structure 2005, 13, 473–482. [Google Scholar] [CrossRef]
- Verdonk, M.L.; Cole, J.C.; Hartshorn, M.J.; Murray, C.W.; Taylor, R.D. Improved Protein-Ligand Docking Using GOLD. Proteins Struct. Funct. Bioinforma. 2003, 52, 609–623. [Google Scholar] [CrossRef] [PubMed]
- Zoete, V.; Cuendet, M.A.; Grosdidier, A.; Michielin, O. SwissParam: A Fast Force Field Generation Tool for Small Organic Molecules. J. Comput. Chem. 2011, 32, 2359–2368. [Google Scholar] [CrossRef] [PubMed]
- José dos Santos Nascimento, I.; Mendonça de Aquino, T.; da Silva Júnior, E.F.; Olimpio de Moura, R. Insights on Microsomal Prostaglandin E2 Synthase 1 (MPGES-1) Inhibitors Using Molecular Dynamics and MM/PBSA Calculations. Lett. Drug Des. Discov. 2023, 20, 1033–1047. [Google Scholar] [CrossRef]
- Santos Nascimento, I.J.d.; Aquino, T.M.d.; Silva-Júnior, E.F.d. Molecular Docking and Dynamics Simulations Studies of a Dataset of NLRP3 Inflammasome Inhibitors. Recent Adv. Inflamm. Allergy Drug Discov. 2022, 16, 80–86. [Google Scholar] [CrossRef]
- dos Santos Nascimento, I.J.; da Silva-Júnior, E.F. TNF-α Inhibitors from Natural Compounds: An Overview, CADD Approaches, and Their Exploration for Anti-Inflammatory Agents. Comb. Chem. High Throughput Screen. 2022, 25, 2317–2340. [Google Scholar] [CrossRef]
- Santos Nascimento, I.J.d.; Aquino, T.M.d.; Silva-Júnior, E.F.d. Repurposing FDA-Approved Drugs Targeting SARS-CoV2 3CLpro: A Study by Applying Virtual Screening, Molecular Dynamics, MM-PBSA Calculations and Covalent Docking. Lett. Drug Des. Discov. 2022, 19, 637–653. [Google Scholar] [CrossRef]
- Silva, L.R.; Guimarães, A.S.; do Nascimento, J.; do Santos Nascimento, I.J.; da Silva, E.B.; McKerrow, J.H.; Cardoso, S.H.; da Silva-Júnior, E.F. Computer-Aided Design of 1,4-Naphthoquinone-Based Inhibitors Targeting Cruzain and Rhodesain Cysteine Proteases. Bioorg. Med. Chem. 2021, 41, 116213. [Google Scholar] [CrossRef] [PubMed]
- Grant, B.J.; Rodrigues, A.P.C.; ElSawy, K.M.; McCammon, J.A.; Caves, L.S.D. Bio3d: An R Package for the Comparative Analysis of Protein Structures. Bioinformatics 2006, 22, 2695–2696. [Google Scholar] [CrossRef]
- Sarma, H.; Mattaparthi, V.S.K. Structure-Based Virtual Screening of High-Affinity ATP-Competitive Inhibitors Against Human Lemur Tyrosine Kinase-3 (LMTK3) Domain: A Novel Therapeutic Target for Breast Cancer. Interdiscip. Sci. Comput. Life Sci. 2019, 11, 527–541. [Google Scholar] [CrossRef]
- Wang, F.; Wu, F.-X.; Li, C.-Z.; Jia, C.-Y.; Su, S.-W.; Hao, G.-F.; Yang, G.-F. ACID: A Free Tool for Drug Repurposing Using Consensus Inverse Docking Strategy. J. Cheminform. 2019, 11, 73. [Google Scholar] [CrossRef]
- Lafayette, E.A.; De Almeida, S.M.V.; Da Rocha Pitta, M.G.; Beltrao, E.I.C.; Da Silva, T.G.; De Moura, R.O.; Da Rocha Pitta, I.; De Carvalho Júnior, L.B.; De Lima, M.D.C.A. Synthesis, DNA Binding and Topoisomerase i Inhibition Activity of Thiazacridine and Imidazacridine Derivatives. Molecules 2013, 18, 15035–15050. [Google Scholar] [CrossRef]
- De Almeida, S.M.V.; Lafayette, E.A.; Da Silva, L.P.B.G.; Da Cruz Amorim, C.A.; De Oliveira, T.B.; Gois Ruiz, A.L.T.; De Carvalho, J.E.; De Moura, R.O.; Carneiro Beltrão, E.I.; De Alves Lima, M.D.C.; et al. Synthesis, DNA Binding, and Antiproliferative Activity of Novel Acridine-Thiosemicarbazone Derivatives. Int. J. Mol. Sci. 2015, 16, 13023–13042. [Google Scholar] [CrossRef]
- Vilková, M.; Prokaiová, M.; Imrich, J. Spontaneous Cyclization of (Acridin-9-Ylmethyl)Thioureas to Spiro [Dihydroacridine-9′(10′H),5-Imidazolidine]-2-Thiones, a Novel Type of Acridine Spirocycles. Tetrahedron 2014, 70, 944–961. [Google Scholar] [CrossRef]
- Casa, D.M.; Scariot, D.B.; Khalil, N.M.; Nakamura, C.V.; Mainardes, R.M. Bovine Serum Albumin Nanoparticles Containing Amphotericin B Were Effective in Treating Murine Cutaneous Leishmaniasis and Reduced the Drug Toxicity. Exp. Parasitol. 2018, 192, 12–18. [Google Scholar] [CrossRef]
- Khattab, S.N.; Khalil, H.H.; Bekhit, A.A.; Abd El-Rahman, M.M.; de la Torre, B.G.; El-Faham, A.; Albericio, F. 1,3,5-Triazino Peptide Derivatives: Synthesis, Characterization, and Preliminary Antileishmanial Activity. ChemMedChem 2018, 13, 725–735. [Google Scholar] [CrossRef]
- de Almeida, L.; Alves, K.F.; Maciel-Rezende, C.M.; Jesus, L.d.O.P.; Pires, F.R.; Junior, C.V.; Izidoro, M.A.; Júdice, W.A.d.S.; dos Santos, M.H.; Marques, M.J. Benzophenone Derivatives as Cysteine Protease Inhibitors and Biological Activity against Leishmania(L.) amazonensis Amastigotes. Biomed. Pharmacother. 2015, 75, 93–99. [Google Scholar] [CrossRef]
- Gentile, D.; Patamia, V.; Scala, A.; Sciortino, M.T.; Piperno, A.; Rescifina, A. Putative Inhibitors of SARS-COV-2 Main Protease from a Library of Marine Natural Products: A Virtual Screening and Molecular Modeling Study. Mar. Drugs 2020, 18, 225. [Google Scholar] [CrossRef]
- Hassab, M.A.E.; Fares, M.; Amin, M.K.A.-H.; Al-Rashood, S.T.; Alharbi, A.; Eskandrani, R.O.; Alkahtani, H.M.; Eldehna, W.M. Toward the Identification of Potential α-Ketoamide Covalent Inhibitors for SARS-CoV-2 Main Protease: Fragment-Based Drug Design and MM-PBSA Calculations. Processes 2021, 9, 1004. [Google Scholar] [CrossRef]
- Varadharajan, V.; Arumugam, G.S.; Shanmugam, S. Isatin-Based Virtual High Throughput Screening, Molecular Docking, DFT, QM/MM, MD and MM-PBSA Study of Novel Inhibitors of SARS-CoV-2 Main Protease. J. Biomol. Struct. Dyn. 2022, 40, 7852–7867. [Google Scholar] [CrossRef] [PubMed]
- Dalal, V.; Dhankhar, P.; Singh, V.; Singh, V.; Rakhaminov, G.; Golemi-Kotra, D.; Kumar, P. Structure-Based Identification of Potential Drugs Against FmtA of Staphylococcus Aureus: Virtual Screening, Molecular Dynamics, MM-GBSA, and QM/MM. Protein J. 2021, 40, 148–165. [Google Scholar] [CrossRef] [PubMed]
- Topliss, J.G. A Manual Method for Applying the Hansch Approach to Drug Design. J. Med. Chem. 1977, 20, 463–469. [Google Scholar] [CrossRef]
- Ortalli, M.; Ilari, A.; Colotti, G.; De Ionna, I.; Battista, T.; Bisi, A.; Gobbi, S.; Rampa, A.; Di Martino, R.M.C.; Gentilomi, G.A.; et al. Identification of Chalcone-Based Antileishmanial Agents Targeting Trypanothione Reductase. Eur. J. Med. Chem. 2018, 152, 527–541. [Google Scholar] [CrossRef]
- de Oliveira, V.V.G.; Aranda de Souza, M.A.; Cavalcanti, R.R.M.; de Oliveira Cardoso, M.V.; Leite, A.C.L.; da Silva Junior, V.A.; de Figueiredo, R.C.B.Q. Study of in Vitro Biological Activity of Thiazoles on Leishmania (Leishmania) infantum. J. Glob. Antimicrob. Resist. 2020, 22, 414–421. [Google Scholar] [CrossRef]
- Courret, N.; Fréhel, C.; Gouhier, N.; Pouchelet, M.; Prina, E.; Roux, P.; Antoine, J.C. Biogenesis of Leishmania-Harbouring Parasitophorus Vacuoles Following Phagocytosis of the Metacyclic Promastigote or Amastigote Stages of the Parasites. J. Cell Sci. 2002, 115, 2303–2316. [Google Scholar] [CrossRef]
- da Silva, A.C.; dos Santos, T.A.R.; da Silva, I.V.B.; de Oliveira, M.V.G.; Moreira, D.R.M.; Leite, A.C.L.; Pereira, V.R.A. Aryl Thiosemicarbazones: In Vitro and Immunomodulatory Activities against L. amazonensis. Exp. Parasitol. 2017, 177, 57–65. [Google Scholar] [CrossRef]
- Araujo Flores, G.V.; Sandoval Pacheco, C.M.; Sosa Ochoa, W.H.; Gomes, C.M.C.; Zúniga, C.; Corbett, C.P.; Laurenti, M.D. Th17 Lymphocytes in Atypical Cutaneous Leishmaniasis Caused by Leishmania (L.) infantum Chagasi in Central America. Parasite Immunol. 2020, 42, e12772. [Google Scholar] [CrossRef]
- Muxel, S.M.; Aoki, J.I.; Fernandes, J.C.R.; Laranjeira-Silva, M.F.; Zampieri, R.A.; Acuña, S.M.; Müller, K.E.; Vanderlinde, R.H.; Floeter-Winter, L.M. Arginine and Polyamines Fate in Leishmania Infection. Front. Microbiol. 2018, 8, 2682. [Google Scholar] [CrossRef]
- Tomiotto-Pellissier, F.; Bortoleti, B.T.d.S.; Assolini, J.P.; Gonçalves, M.D.; Carloto, A.C.M.; Miranda-Sapla, M.M.; Conchon-Costa, I.; Bordignon, J.; Pavanelli, W.R. Macrophage Polarization in Leishmaniasis: Broadening Horizons. Front. Immunol. 2018, 9, 2529. [Google Scholar] [CrossRef]
- Mirzaei, A.; Maleki, M.; Masoumi, E.; Maspi, N. A Historical Review of the Role of Cytokines Involved in Leishmaniasis. Cytokine 2021, 145, 155297. [Google Scholar] [CrossRef] [PubMed]
- de Oliveira Cardoso, J.M.; de Brito, R.C.F.; Costa, A.F.P.; Siqueira Mathias, F.A.; Soares Reis, L.E.; Vieira, J.F.P.; de Oliveira Aguiar Soares, R.D.; Reis, A.B.; Roatt, B.M. IL-10 Receptor Blockade Controls the in Vitro Infectivity of Leishmania Infantum and Promotes a Th1 Activation in PBMC of Dogs with Visceral Leishmaniasis. Mol. Immunol. 2021, 137, 20–27. [Google Scholar] [CrossRef]
- Maspi, N.; Abdoli, A.; Ghaffarifar, F. Pro- and Anti-Inflammatory Cytokines in Cutaneous Leishmaniasis: A Review. Pathog. Glob. Health 2016, 110, 247–260. [Google Scholar] [CrossRef] [PubMed]
- Mesquita, I.; Ferreira, C.; Barbosa, A.M.; Ferreira, C.M.; Moreira, D.; Carvalho, A.; Cunha, C.; Rodrigues, F.; Dinis-Oliveira, R.J.; Estaquier, J.; et al. The Impact of IL-10 Dynamic Modulation on Host Immune Response against Visceral Leishmaniasis. Cytokine 2018, 112, 16–20. [Google Scholar] [CrossRef] [PubMed]
- Espir, T.T.; Figueira, L.d.P.; Naiff, M.d.F.; Costa, A.G.d.; Ramalho-Ortigão, M.; Malheiro, A.; Franco, A.M.R. The Role of Inflammatory, Anti-Inflammatory, and Regulatory Cytokines in Patients Infected with Cutaneous Leishmaniasis in Amazonas State, Brazil. J. Immunol. Res. 2014, 2014, 10. [Google Scholar] [CrossRef]
- Hurst, S.M.; Wilkinson, T.S.; McLoughlin, R.M.; Jones, S.; Horiuchi, S.; Yamamoto, N.; Rose-John, S.; Fuller, G.M.; Topley, N.; Jones, S.A. IL-6 and Its Soluble Receptor Orchestrate a Temporal Switch in the Pattern of Leukocyte Recruitment Seen during Acute Inflammation. Immunity 2001, 14, 705–714. [Google Scholar] [CrossRef]
- Banerjee, A.; Bhattacharya, P.; Joshi, A.B.; Ismail, N.; Dey, R.; Nakhasi, H.L. Role of Pro-Inflammatory Cytokine IL-17 in Leishmania Pathogenesis and in Protective Immunity by Leishmania Vaccines. Cell. Immunol. 2016, 309, 37–41. [Google Scholar] [CrossRef]
- Pedraza-Zamora, C.P.; Delgado-Domínguez, J.; Zamora-Chimal, J.; Becker, I. Th17 Cells and Neutrophils: Close Collaborators in Chronic Leishmania Mexicana Infections Leading to Disease Severity. Parasite Immunol. 2017, 39, e12420. [Google Scholar] [CrossRef]
- Kima, P.E. Leishmania Molecules That Mediate Intracellular Pathogenesis. Microbes Infect. 2014, 16, 721–726. [Google Scholar] [CrossRef]
- Genestra, M.; Echevarria, A.; Cysne-Finkelstein, L.; Vignólio-Alves, L.; Leon, L.L. Effect of Amidine Derivatives on Nitric Oxide Production by Leishmania Amazonensis Promastigotes and Axenic Amastigotes. Nitric Oxide–Biol. Chem. 2003, 8, 1–6. [Google Scholar] [CrossRef]
- Giudice, A.; Camada, I.; Leopoldo, P.T.G.; Pereira, J.M.B.; Riley, L.W.; Wilson, M.E.; Ho, J.L.; de Jesus, A.R.; Carvalho, E.M.; Almeida, R.P. Resistance of Leishmania (Leishmania) amazonensis and Leishmania (Viannia) braziliensis to Nitric Oxide Correlates with Disease Severity in Tegumentary Leishmaniasis. BMC Infect. Dis. 2007, 7, 7. [Google Scholar] [CrossRef]
- Perrella Balestieri, F.M.; Pires Queiroz, A.R.; Scavone, C.; Assis Costa, V.M.; Barral-Netto, M.; Abrahamsohn, I.d.A. Leishmania (L.) amazonensis-Induced Inhibition of Nitric Oxide Synthesis in Host Macrophages. Microbes Infect. 2002, 4, 23–29. [Google Scholar] [CrossRef]
- Roma, E.H.; Macedo, J.P.; Goes, G.R.; Gonçalves, J.L.; Castro, W.D.; Cisalpino, D.; Vieira, L.Q. Impact of Reactive Oxygen Species (ROS) on the Control of Parasite Loads and Inflammation in Leishmania amazonensis Infection. Parasites Vectors 2016, 9, 193. [Google Scholar] [CrossRef]
- Bortoleti, B.T.d.S.; Gonçalves, M.D.; Tomiotto-Pellissier, F.; Contato, V.M.; Silva, T.F.; de Matos, R.L.N.; Detoni, M.B.; Rodrigues, A.C.J.; Carloto, A.C.; Lazarin, D.B.; et al. Solidagenone Acts on Promastigotes of L. amazonensis by Inducing Apoptosis-like Processes on Intracellular Amastigotes by IL-12p70/ROS/NO Pathway Activation. Phytomedicine 2021, 85, 153536. [Google Scholar] [CrossRef]
- Rodrigues, R.R.L.; Nunes, T.A.L.; de Araújo, A.R.; Marinho Filho, J.D.B.; da Silva, M.V.; Carvalho, F.A.d.A.; Pessoa, O.D.L.; Freitas, H.P.S.; Rodrigues, K.A.d.F.; Araújo, A.J. Antileishmanial Activity of Cordiaquinone E towards Leishmania (Leishmania) amazonensis. Int. Immunopharmacol. 2021, 90, 107124. [Google Scholar] [CrossRef]
- Bivona, A.E.; Czentner, L.; Alberti, A.S.; Cerny, N.; Landaburu, A.C.C.; Nevot, C.; Estévez, O.; Marco, J.D.; Basombrio, M.A.; Malchiodi, E.L.; et al. Recombinant Cysteine Proteinase B from Leishmania Braziliensis and Its Domains: Promising Antigens for Serodiagnosis of Cutaneous and Visceral Leishmaniasis in Dogs. J. Clin. Microbiol. 2019, 57, 1–13. [Google Scholar] [CrossRef]
- Gomes, C.B.; Silva, F.S.; Charret, K.d.S.; Pereira, B.A.S.; Finkelstein, L.C.; Santos-de-Souza, R.; de Castro Côrtes, L.M.; Pereira, M.C.S.; Rodrigues de Oliveira, F.O.; Alves, C.R. Increasing in Cysteine Proteinase B Expression and Enzymatic Activity during in Vitro Differentiation of Leishmania (Viannia) braziliensis: First Evidence of Modulation during Morphological Transition. Biochimie 2017, 133, 28–36. [Google Scholar] [CrossRef]
- Somanna, A.; Mundodi, V.; Gedamu, L. Functional Analysis of Cathepsin B-like Cysteine Proteases from Leishmania Donovani Complex: Evidence for the Activation of Latent Transforming Growth Factor β. J. Biol. Chem. 2002, 277, 25305–25312. [Google Scholar] [CrossRef]
- Buxbaum, L.U.; Denise, H.; Coombs, G.H.; Alexander, J.; Mottram, J.C.; Scott, P. Cysteine Protease B of Leishmania Mexicana Inhibits Host Th1 Responses and Protective Immunity. J. Immunol. 2003, 171, 3711–3717. [Google Scholar] [CrossRef]
- Mottram, J.C.; Brooks, D.R.; Coombs, G.H. Roles of Cysteine Proteinases of Trypanosomes and Leishmania in Host-Parasite Interactions. Curr. Opin. Microbiol. 1998, 1, 455–460. [Google Scholar] [CrossRef]
Compounds | L. infantum IC50PRO (µM) | L. amazonensis IC50PRO (µM) | HC50 (µM) |
---|---|---|---|
AMTAC-01 | 6.27 | 1.23 | >400 |
AMTAC-02 | 2.22 | 0.73 | >400 |
AMTAC-06 | 13.8 | 0.75 | >400 |
ACMD-01 | 3.90 | ND * | >400 |
ACMD-03 | 7.82 | 10.95 | >400 |
ACMD-06 | 3.50 | 234.95 | >400 |
ANFO B | 0.05 | 1.53 | 24.25 |
Compound | IC50AMA (µM) | CC50 (µM) | SI |
---|---|---|---|
AMTAC-02 | 13.50 | 569.50 | 39.6 |
ACMD-03 | 10.47 | 27.22 | 2.6 |
ANFO B | 1.08 | 3.09 | 2.8 |
Target | Fit Score AMTAC-02 | Fit Score ACMD-03 | Standard |
---|---|---|---|
4APN (TyR) | 68.58 | 60.81 | 94.51 |
3L4D (CYP51) | 23.84 | 41.40 | 63.18 |
2B9S (Topo I) | 52.55 | 53.00 | 63.98 * |
1TL8 (Topo I human) | 64.35 | 57.91 | 82.56 |
CPBLa | 44.71 | 50.05 | 47.77 * |
Interaction Parameter | Value for ACMD-03 (in kJ/mol) |
---|---|
ΔGbind | −65.225 ± 8.181 |
SASA energy | −11.926 ± 1.205 |
Polar solvation energy | 58.801 ± 8.727 |
Electrostatic energy | −4.489 ± 6.560 |
van der Waal energy | −107.611 ± 12.071 |
Disclaimer/Publisher’s Note: The statements, opinions and data contained in all publications are solely those of the individual author(s) and contributor(s) and not of MDPI and/or the editor(s). MDPI and/or the editor(s) disclaim responsibility for any injury to people or property resulting from any ideas, methods, instructions or products referred to in the content. |
© 2025 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
Share and Cite
Albino, S.; Nobre, M.; da Silva, J.; Reis, M.d.; Nascimento, M.; de Oliveira, M.; Borges, T.; Albuquerque, L.; Kuckelhaus, S.; Alves, L.; et al. Synthesis, Biological Evaluation, Molecular Dynamics, and QM-MM Calculation of Spiro-Acridine Derivatives Against Leishmaniasis. Microorganisms 2025, 13, 1297. https://doi.org/10.3390/microorganisms13061297
Albino S, Nobre M, da Silva J, Reis Md, Nascimento M, de Oliveira M, Borges T, Albuquerque L, Kuckelhaus S, Alves L, et al. Synthesis, Biological Evaluation, Molecular Dynamics, and QM-MM Calculation of Spiro-Acridine Derivatives Against Leishmaniasis. Microorganisms. 2025; 13(6):1297. https://doi.org/10.3390/microorganisms13061297
Chicago/Turabian StyleAlbino, Sonaly, Michelangela Nobre, Jamire da Silva, Malu dos Reis, Maria Nascimento, Mayara de Oliveira, Tatiana Borges, Lucas Albuquerque, Selma Kuckelhaus, Luis Alves, and et al. 2025. "Synthesis, Biological Evaluation, Molecular Dynamics, and QM-MM Calculation of Spiro-Acridine Derivatives Against Leishmaniasis" Microorganisms 13, no. 6: 1297. https://doi.org/10.3390/microorganisms13061297
APA StyleAlbino, S., Nobre, M., da Silva, J., Reis, M. d., Nascimento, M., de Oliveira, M., Borges, T., Albuquerque, L., Kuckelhaus, S., Alves, L., dos Santos, F., de Lima, M., Nascimento, I., da Silva, T., & de Moura, R. (2025). Synthesis, Biological Evaluation, Molecular Dynamics, and QM-MM Calculation of Spiro-Acridine Derivatives Against Leishmaniasis. Microorganisms, 13(6), 1297. https://doi.org/10.3390/microorganisms13061297