Submit Manuscript  

Article Details


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

[ Vol. 18 , Issue. 2 ]

Author(s):

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* and João X. de Araújo-Júnior   Pages 151 - 169 ( 19 )

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 in 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.

Objectives: 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 "inhouse" 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 in progress, which will help choose the best hits for in vivo experiments.

Keywords:

Aminoguanidine hydrazone, thiosemicarbazone, antileishmanial activity, Leishmania chagasi, molecular docking, structure-activity relationship.

Affiliation:

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



Read Full-Text article