Síntese, Atividade Antileshmania E Citotóxica De Hidrazonas Derivadas De Aldeídos Naturais

Abstract

SYNTHESIS, ANTILESHMANIA AND CYTOTOXIC ACTIVITY OF HYDRAZONES FROM NATURAL ALDEHYDES. Leishmaniasis is endemic anthropozoonosis considered to be a severe public health problem. The treatment with pentavalent antimonials presents high toxicity motivating the search for effective and less toxic drugs. Hydrazones and N-acylhydrazones are functional groups that are prominent in Medicinal Chemistry, including as antiprotozoals. In this context, five hydrazones derived from the natural aldehydes were synthesized and the molecular structures were suitably determined to employ uni and bidimensional 1 H and 13 C NMR techniques. The antileishmanial activity of all hydrazones was determined against promastigote forms of Leishmania amazonensis, and the compounds HDZ-3, HDZ-4, and HDZ-5 showed the best results, with IC 50 of 9.00, 38.10 and 26.30 μM, respectively. In the cytotoxic evaluation against RAW macrophages, HDZ-4 presented the least cytotoxic (CC 50 = 222.24 μM) and the higher selectivity. Lipinski's descriptors of the hydrazones were calculated, and the compounds HDZ-3 and HDZ-5 were more promising. These hydrazones are hybrids of natural aldehydes with drugs, the first is the result of the junction of the cinnamaldehyde with isoniazid, and the second of the vanillin with hydralazine. The results highlighted the Markush isonicotinoylhydrazone and phthalazinylhydrazone groups, molecular structures that are present in HDZ-3 and HDZ-5 and are therefore considered innovators in the development of antileishmanial drugs.

Hydrazones derived from natural aldehydes: in vitro cytotoxic evaluation and in silico pharmacokinetic predictions

“…It was verified that only the VAN-2 compound presented intermediate absorption when analyzed in this in silico model (20% < HIA < 70%). This high rate of intestinal absorption reflects LogP: a obtained from Souza et al [12] b calculated in ChemDrawn®. HIA: Low absorption 0.0-20.0%; moderate absorption 20.0-70.0%; excellent absorption 70.0-100.0% [24].…”

“…A series composed of six hydrazones was planned by molecular hybridization using the natural aldehydes vanillin (VAN-1 and VAN-2) and cinnamaldehyde (CIN-1 -CIN-4), which are synthesized as described by Souza et al (2020) [12] (figure 1). With the precursor vanillin, two hydrazones called VAN-1 and VAN-2, with yields of 98.0% and 70.0%, respectively, were obtained.…”

“…The hydrazones were obtained through the methodology described by Souza et al [12], from the reaction between vanillin and cinnamaldehyde with hydrazines. The six hydrazones obtained were named: vanillin 1-phthalazinylhydrazone (VAN-1), vanillin 2,4-dinitrophenylhydrazone (VAN-2), cinnamaldehyde phenylhydrazone (CIN-1), cinnamaldehyde isonicotinohydrazone (CIN-2), cinnamaldehyde 1-phthalazinylhydrazone (CIN-3), and cinnamaldehyde 2,4-dinitrophenylhydrazone (CIN-4).…”

Synthesis and antileishmanial activity of naphthoquinone-based hybrids

“…For the synthesis, all the reagents used were obtained from commercial sources and used without prior purification, with the exception of hydralazine hydrochloride, which was obtained from Apresolina ® pills (Anovis Industrial Farmacêutica Ltda) [10,13]. The synthesized substances had its melting temperatures determined in triplicate using analog fusiometer, model PFM-II (MS Tecnopon ® instrumentation).…”

“…In a study published this year, Souza et al (2020) pointed out the relevance of the presence of isonicotinohydrazone and phthalazinylhydrazone nuclei in the structures of compounds for the antileishmanial activity. In this work, the authors synthesized five hydrazones and evaluated in vitro the activity against the promastigote form of L. amazonensis [10].…”