Hybrid furoxanyl N-acylhydrazone derivatives as hits for the development of neglected diseases drug candidates

Paola Hernández, Rosario Rojas, Robert H Gilman, Michel Sauvain, Lidia M. Lima, Eliezer J. Barreiro, Mercedes González, Hugo Cerecetto

Research output: Contribution to journalArticle

Abstract

Neglected diseases represent a major health problem. It is estimated that one third of the world population is infected with tuberculosis and additionally Leishmaniosis and Chagas disease affect approximately 30 million people. N-Acylhydrazone moiety is a repeated functional group present in several prototypes and drug candidates for these neglected diseases. On the other hand, furoxan system has been studied as pharmacophore for Leishmaniosis and Chagas diseases. Here we report on the design and preparation of forty hybrid furoxanyl N-acylhydrazones and on their activity on Mycobacterium tuberculosis, H37Rv and MDR strains, Trypanosoma cruzi, and Leishmania amazonensis. Among them, four derivatives displayed excellent to good selectivity indexes against the three different microorganisms. Hybrid compound N′-(4-phenyl-3- furoxanylmethylidene)isoniazide 9 showed the best antibacterial profile with MIC value 4.5 lesser than the value for the reference isoniazid against MDR strain. Furoxanyl N-acylhydrazone (E)-2-methyl-N′-(4-phenyl-3- furoxanylmethylidene)-4H-imidazo[1,2-a]pyridine-3-carbohydrazide 15 was ten-fold more potent against T. cruzi Amastigotes than the standard drug nifurtimox. On the other hand, derivatives (E)-N′-(5-benzofuroxanylmethylidene)benzo[d] [1,3]dioxole-5-carbohydrazide 25 and (E)-N′-(4-hydroxy-3- methoxyphenylmethylidene)-3-methylfuroxan-4-carbohydrazide 37 emerged as leads for the development of new leishmanicidal agents. The adequate stability, in simulated biological system and plasma, and the lack of mutagenicity of these derivatives allow us to propose them as candidates for further pre-clinical studies.

Original languageEnglish (US)
Pages (from-to)64-74
Number of pages11
JournalEuropean Journal of Medicinal Chemistry
Volume59
DOIs
StatePublished - Jan 2013
Externally publishedYes

Fingerprint

Neglected Diseases
Leishmaniasis
Chagas Disease
Trypanosoma cruzi
Derivatives
Nifurtimox
Pharmaceutical Preparations
Leishmania
Isoniazid
Mycobacterium tuberculosis
Reference Values
Tuberculosis
Biological systems
Medical problems
Microorganisms
Functional groups
Health
Plasmas
Population
carbohydrazide

Keywords

  • Anti-Leishmania
  • Anti-M. tuberculosis
  • Anti-T. cruzi
  • Furoxane
  • N-Acylhydrazone

ASJC Scopus subject areas

  • Drug Discovery
  • Organic Chemistry
  • Pharmacology

Cite this

Hybrid furoxanyl N-acylhydrazone derivatives as hits for the development of neglected diseases drug candidates. / Hernández, Paola; Rojas, Rosario; Gilman, Robert H; Sauvain, Michel; Lima, Lidia M.; Barreiro, Eliezer J.; González, Mercedes; Cerecetto, Hugo.

In: European Journal of Medicinal Chemistry, Vol. 59, 01.2013, p. 64-74.

Research output: Contribution to journalArticle

Hernández, Paola ; Rojas, Rosario ; Gilman, Robert H ; Sauvain, Michel ; Lima, Lidia M. ; Barreiro, Eliezer J. ; González, Mercedes ; Cerecetto, Hugo. / Hybrid furoxanyl N-acylhydrazone derivatives as hits for the development of neglected diseases drug candidates. In: European Journal of Medicinal Chemistry. 2013 ; Vol. 59. pp. 64-74.
@article{d9b718b350bf4982bd238b720b142f57,
title = "Hybrid furoxanyl N-acylhydrazone derivatives as hits for the development of neglected diseases drug candidates",
abstract = "Neglected diseases represent a major health problem. It is estimated that one third of the world population is infected with tuberculosis and additionally Leishmaniosis and Chagas disease affect approximately 30 million people. N-Acylhydrazone moiety is a repeated functional group present in several prototypes and drug candidates for these neglected diseases. On the other hand, furoxan system has been studied as pharmacophore for Leishmaniosis and Chagas diseases. Here we report on the design and preparation of forty hybrid furoxanyl N-acylhydrazones and on their activity on Mycobacterium tuberculosis, H37Rv and MDR strains, Trypanosoma cruzi, and Leishmania amazonensis. Among them, four derivatives displayed excellent to good selectivity indexes against the three different microorganisms. Hybrid compound N′-(4-phenyl-3- furoxanylmethylidene)isoniazide 9 showed the best antibacterial profile with MIC value 4.5 lesser than the value for the reference isoniazid against MDR strain. Furoxanyl N-acylhydrazone (E)-2-methyl-N′-(4-phenyl-3- furoxanylmethylidene)-4H-imidazo[1,2-a]pyridine-3-carbohydrazide 15 was ten-fold more potent against T. cruzi Amastigotes than the standard drug nifurtimox. On the other hand, derivatives (E)-N′-(5-benzofuroxanylmethylidene)benzo[d] [1,3]dioxole-5-carbohydrazide 25 and (E)-N′-(4-hydroxy-3- methoxyphenylmethylidene)-3-methylfuroxan-4-carbohydrazide 37 emerged as leads for the development of new leishmanicidal agents. The adequate stability, in simulated biological system and plasma, and the lack of mutagenicity of these derivatives allow us to propose them as candidates for further pre-clinical studies.",
keywords = "Anti-Leishmania, Anti-M. tuberculosis, Anti-T. cruzi, Furoxane, N-Acylhydrazone",
author = "Paola Hern{\'a}ndez and Rosario Rojas and Gilman, {Robert H} and Michel Sauvain and Lima, {Lidia M.} and Barreiro, {Eliezer J.} and Mercedes Gonz{\'a}lez and Hugo Cerecetto",
year = "2013",
month = "1",
doi = "10.1016/j.ejmech.2012.10.047",
language = "English (US)",
volume = "59",
pages = "64--74",
journal = "European Journal of Medicinal Chemistry",
issn = "0223-5234",
publisher = "Elsevier Masson SAS",

}

TY - JOUR

T1 - Hybrid furoxanyl N-acylhydrazone derivatives as hits for the development of neglected diseases drug candidates

AU - Hernández, Paola

AU - Rojas, Rosario

AU - Gilman, Robert H

AU - Sauvain, Michel

AU - Lima, Lidia M.

AU - Barreiro, Eliezer J.

AU - González, Mercedes

AU - Cerecetto, Hugo

PY - 2013/1

Y1 - 2013/1

N2 - Neglected diseases represent a major health problem. It is estimated that one third of the world population is infected with tuberculosis and additionally Leishmaniosis and Chagas disease affect approximately 30 million people. N-Acylhydrazone moiety is a repeated functional group present in several prototypes and drug candidates for these neglected diseases. On the other hand, furoxan system has been studied as pharmacophore for Leishmaniosis and Chagas diseases. Here we report on the design and preparation of forty hybrid furoxanyl N-acylhydrazones and on their activity on Mycobacterium tuberculosis, H37Rv and MDR strains, Trypanosoma cruzi, and Leishmania amazonensis. Among them, four derivatives displayed excellent to good selectivity indexes against the three different microorganisms. Hybrid compound N′-(4-phenyl-3- furoxanylmethylidene)isoniazide 9 showed the best antibacterial profile with MIC value 4.5 lesser than the value for the reference isoniazid against MDR strain. Furoxanyl N-acylhydrazone (E)-2-methyl-N′-(4-phenyl-3- furoxanylmethylidene)-4H-imidazo[1,2-a]pyridine-3-carbohydrazide 15 was ten-fold more potent against T. cruzi Amastigotes than the standard drug nifurtimox. On the other hand, derivatives (E)-N′-(5-benzofuroxanylmethylidene)benzo[d] [1,3]dioxole-5-carbohydrazide 25 and (E)-N′-(4-hydroxy-3- methoxyphenylmethylidene)-3-methylfuroxan-4-carbohydrazide 37 emerged as leads for the development of new leishmanicidal agents. The adequate stability, in simulated biological system and plasma, and the lack of mutagenicity of these derivatives allow us to propose them as candidates for further pre-clinical studies.

AB - Neglected diseases represent a major health problem. It is estimated that one third of the world population is infected with tuberculosis and additionally Leishmaniosis and Chagas disease affect approximately 30 million people. N-Acylhydrazone moiety is a repeated functional group present in several prototypes and drug candidates for these neglected diseases. On the other hand, furoxan system has been studied as pharmacophore for Leishmaniosis and Chagas diseases. Here we report on the design and preparation of forty hybrid furoxanyl N-acylhydrazones and on their activity on Mycobacterium tuberculosis, H37Rv and MDR strains, Trypanosoma cruzi, and Leishmania amazonensis. Among them, four derivatives displayed excellent to good selectivity indexes against the three different microorganisms. Hybrid compound N′-(4-phenyl-3- furoxanylmethylidene)isoniazide 9 showed the best antibacterial profile with MIC value 4.5 lesser than the value for the reference isoniazid against MDR strain. Furoxanyl N-acylhydrazone (E)-2-methyl-N′-(4-phenyl-3- furoxanylmethylidene)-4H-imidazo[1,2-a]pyridine-3-carbohydrazide 15 was ten-fold more potent against T. cruzi Amastigotes than the standard drug nifurtimox. On the other hand, derivatives (E)-N′-(5-benzofuroxanylmethylidene)benzo[d] [1,3]dioxole-5-carbohydrazide 25 and (E)-N′-(4-hydroxy-3- methoxyphenylmethylidene)-3-methylfuroxan-4-carbohydrazide 37 emerged as leads for the development of new leishmanicidal agents. The adequate stability, in simulated biological system and plasma, and the lack of mutagenicity of these derivatives allow us to propose them as candidates for further pre-clinical studies.

KW - Anti-Leishmania

KW - Anti-M. tuberculosis

KW - Anti-T. cruzi

KW - Furoxane

KW - N-Acylhydrazone

UR - http://www.scopus.com/inward/record.url?scp=84870205359&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84870205359&partnerID=8YFLogxK

U2 - 10.1016/j.ejmech.2012.10.047

DO - 10.1016/j.ejmech.2012.10.047

M3 - Article

C2 - 23202852

AN - SCOPUS:84870205359

VL - 59

SP - 64

EP - 74

JO - European Journal of Medicinal Chemistry

JF - European Journal of Medicinal Chemistry

SN - 0223-5234

ER -