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de Aquino TM, França PHB, Rodrigues ÉEES, et al. Synthesis, Antileishmanial Activity and in silico Studies of Aminoguanidine Hydrazones (AGH) and Thiosemicarbazones (TSC) Against Leishmania chagasi Amastigotes. Med Chem. 2021;doi: 10.2174/1573406417666210216154428.
de Aquino, T. M., França, P. H. B., Rodrigues, �. �. E. E. S., Nascimento, I. J. S., Santos-Júnior, P. F. S., Aquino, P. G. V., Santos, M. S., Queiroz, A. C., Araújo, M. V., Alexandre-Moreira, M. S., Rodrigues, R. R. L., Rodrigues, K. A. F., Freitas, J. D., Bricard, J., Meneghetti, M. R., Bourguignon, J. J., Schmitt, M., da Silva-Júnior, E. F., & de Araújo-Júnior, J. X. (2021). Synthesis, Antileishmanial Activity and in silico Studies of Aminoguanidine Hydrazones (AGH) and Thiosemicarbazones (TSC) Against Leishmania chagasi Amastigotes. Medicinal chemistry (Shariqah (United Arab Emirates)), . https://doi.org/10.2174/1573406417666210216154428
de Aquino, Thiago M, et al. "Synthesis, Antileishmanial Activity and in silico Studies of Aminoguanidine Hydrazones (AGH) and Thiosemicarbazones (TSC) Against Leishmania chagasi Amastigotes." Medicinal chemistry (Shariqah (United Arab Emirates)) vol. (2021). doi: https://doi.org/10.2174/1573406417666210216154428
de Aquino TM, França PHB, Rodrigues ÉEES, Nascimento IJS, Santos-Júnior PFS, Aquino PGV, Santos MS, Queiroz AC, Araújo MV, Alexandre-Moreira MS, Rodrigues RRL, Rodrigues KAF, Freitas JD, Bricard J, Meneghetti MR, Bourguignon JJ, Schmitt M, da Silva-Júnior EF, de Araújo-Júnior JX. Synthesis, Antileishmanial Activity and in silico Studies of Aminoguanidine Hydrazones (AGH) and Thiosemicarbazones (TSC) Against Leishmania chagasi Amastigotes. Med Chem. 2021 Feb 16; doi: 10.2174/1573406417666210216154428. Epub 2021 Feb 16. PMID: 33593264.
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Med Chem. 2021 Feb 16; doi: 10.2174/1573406417666210216154428. Epub 2021 Feb 16.

Synthesis, Antileishmanial Activity and in silico Studies of Aminoguanidine Hydrazones (AGH) and Thiosemicarbazones (TSC) Against Leishmania chagasi Amastigotes.

Medicinal chemistry (Shariqah (United Arab Emirates))

Thiago M de Aquino, Paulo H B França, Érica E E S Rodrigues, Igor J S Nascimento, Paulo F S Santos-Júnior, Pedro G V Aquino, Mariana S Santos, Aline C Queiroz, Morgana V Araújo, Magna S Alexandre-Moreira, Raiza R L Rodrigues, Klinger A F Rodrigues, Johnnatan D Freitas, Jacques Bricard, Mario R Meneghetti, Jean-Jacques Bourguignon, Martine Schmitt, Edeildo F da Silva-Júnior, João X de Araújo-Júnior

Affiliations

  1. Laboratory of Medicinal Chemistry, Institute of Pharmaceutical Sciences, Federal University of Alagoas, 57072-900, Maceió-AL. Brazil.
  2. Federal Rural University of Pernambuco, Garanhuns-PE, 55292-270. Brazil.
  3. Laboratory of Pharmacology and Immunology, Institute of Biological and Health Sciences, Federal University of Alagoas, 57072-900, Maceió-AL. Brazil.
  4. Laboratory of Infectious Diseases, Federal University of Parnaíba Delta, 64202-020, Parnaíba-PI. Brazil.
  5. Instrumental Analysis Laboratory, Federal Institute of Alagoas, Campus Maceió, Ferroviário Avenue, 57020-600, Maceió-AL. Brazil.
  6. Laboratoire d'Innovation thérapeutique, UMR 7200, Labex Medalis, CNRS, Université de Strasbourg, Faculté de Pharmacie, 74 route du Rhin, BP 60024, 67401 Illkirch. France.
  7. Institute of Chemistry and Biotechnology, Federal University of Alagoas, 57072-90 0, Maceió-AL. Brazil.

PMID: 33593264 DOI: 10.2174/1573406417666210216154428

Abstract

BACKGROUND: Leishmaniasis is a worldwide health problem, highly endemic in developing countries. Among the four main clinical forms of the disease, visceral leishmaniasis is the most severe, fatal in 95% of cases. The undesired side-effects from first-line chemotherapy and the reported drug resistance search for effective drugs that can replace or supplement those currently used an urgent need. Aminoguanidine hydrazones (AGH's) have been explored for exhibiting a diverse spectrum of biological activities, in particular the antileishmanial activity of MGBG. The bioisosteres thiosemicarbazones (TSC's) offer a similar biological activity diversity, including antiprotozoal effects against Leishmania species and Trypanosoma cruzi.

OBJECTIVE: Considering the impact of leishmaniasis worldwide, this work aimed to design, synthesize, and perform a screening upon L. chagasi amastigotes and for the cytotoxicity of the small "in-house" library of both AGH and TSC derivatives and their structurally-related compounds.

METHOD: A set of AGH's (3-7), TSC's (9, 10), and semicarbazones (11) were initially synthesized. Subsequently, different semi-constrained analogs were designed and also prepared, including thiazolidines (12), dihydrothiazines (13), imidazolines (15), pyrimidines (16, 18) azines (19, 20), and benzotriazepinones (23-25). All intermediates and target compounds were obtained with satisfactory yields and exhibited spectral data consistent with their structures. All final compounds were evaluated against L. chagasi amastigotes and J774.A1 cell line. Molecular docking was performed towards trypanothione reductase using GOLD® software.

RESULT: The AGH's 3i, 4a, and 5d, and the TSC's 9i, 9k, and 9o were selected as valuable hits. These compounds presented antileishmanial activity compared with pentamidine, showing IC50 values ranged from 0.6 to 7.27 μM, maximal effects up to 55.3%, and satisfactory SI values (ranged from 11 to 87). On the other hand, most of the resulting semi-constrained analogs were found cytotoxic or presented reduced antileishmanial activity. In general, TSC class is more promising than its isosteric AGH analogs, and the beneficial aromatic substituent effects are not similar in both series. In silico studies have suggested that these hits are capable of inhibiting the trypanothione reductase from the amastigote forms.

CONCLUSION: The promising antileishmanial activity of three AGH's and three TSC's was characterized. These compounds presented antileishmanial activity compared with PTD, showing IC50 values ranged from 0.6 to 7.27 μM, and satisfactory SI values. Further pharmacological assays involving other Leishmania strains are under progress, which will help to choose the best hits for in vivo experiments.

Copyright© Bentham Science Publishers; For any queries, please email at [email protected].

Keywords: Antileishmanial Activity and in silico Studies of Aminoguanidine Hydrazones (AGH) and Thiosemicarbazones (TSC) Against Leishmania chagasi Amastigotes; Synthesis

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