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.
authors.affiliation: Grupo de Química Medicinal, Laboratorio de Química Orgánica, Facultad de Ciencias-Facultad de Química, Universidad de la República, Igua 4225, 11400 Montevideo, Uruguay.
authors.forename: Paola
authors.initials: P
authors.lastname: Hernández
authors.forename: Rosario
authors.initials: R
authors.lastname: Rojas
authors.forename: Robert H
authors.initials: RH
authors.lastname: Gilman
authors.forename: Michel
authors.initials: M
authors.lastname: Sauvain
authors.forename: Lidia M
authors.initials: LM
authors.lastname: Lima
authors.forename: Eliezer J
authors.initials: EJ
authors.lastname: Barreiro
authors.forename: Mercedes
authors.initials: M
authors.lastname: González
authors.forename: Hugo
authors.initials: H
authors.lastname: Cerecetto
mesh_terms: D000890:Anti-Infective Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D015195:Drug Design; D004355:Drug Stability; D006835:Hydrazones / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D020128:Inhibitory Concentration 50; D007891:Leishmania / Q000187:drug effects; D009169:Mycobacterium tuberculosis / Q000187:drug effects; D058069:Neglected Diseases / Q000188:drug therapy; D010069:Oxadiazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D014349:Trypanosoma cruzi / Q000187:drug effects
chemical_list: D000890:Anti-Infective Agents; D006835:Hydrazones; D010069:Oxadiazoles; C010166:furoxans