title: Antiplatelet properties of novel N-substituted-phenyl-1,2,3-triazole-4-acylhydrazone derivatives.
abstract: This paper describes the design, synthesis and pharmacological evaluation of new N-acylhydrazone (NAH) compounds, belonging to the N-substituted-phenyl-1,2,3-triazole-4-acylhydrazone class (2a-p). Classical heteroaromatic ring bioisosterism strategies were applied to the previously reported N-phenylpyrazolyl-4-acylhydrazone derivative 1, elected as lead-compound due to its important anti-aggregating profile on arachidonic acid induced platelet aggregation (IC(50)=24+/-0.5 micro M), from which emerge this new series 2. These new compounds 2a-p were readily synthesized, characterized and tested on platelet aggregation assays induced by collagen (5 micro g/mL), ADP (5 micro M) and arachidonic acid (100 micro M) in rabbit citrated platelet-rich plasma. Compounds 2b, 2d, and 2h were found to be the most potent, exhibiting a significant antiplatelet activity on arachidonic acid- and collagen-induced platelet aggregation. In addition, these new antiplatelet agents are free of gastric ulcerogenic effect and presented discrete anti-inflammatory and analgesic properties. The N-para-chlorophenyltriazolyl-4-acylhydrazone compound 2h produced the highest inhibitory effect on collagen (IC(50)=21.6+/-0.4 micro M) and arachidonic acid-induced platelet aggregation (IC(50)=2.2+/-0.06 micro M), suggesting that the nature of the substituent on the phenyl ring of the N-heteroaromatic system of NAH moiety may be an important structural requirement for the improvement of antiplatelet activity, in comparison with lead-series 1.
authors.affiliation: Laboratório de Avaliação e Síntese de Substâncias Biotivas (LASSBio), Faculdade de Farmácia, Universidade Federal do Rio de Janeiro, PO Box 68006, 21944-971, Rio de Janeiro, RJ, Brazil.
authors.forename: Anna C
authors.initials: AC
authors.lastname: Cunha
authors.forename: Juliana M
authors.initials: JM
authors.lastname: Figueiredo
authors.forename: Jorge L M
authors.initials: JL
authors.lastname: Tributino
authors.forename: Ana L P
authors.initials: AL
authors.lastname: Miranda
authors.forename: Helena C
authors.initials: HC
authors.lastname: Castro
authors.forename: Russolina B
authors.initials: RB
authors.lastname: Zingali
authors.forename: Carlos A M
authors.initials: CA
authors.lastname: Fraga
authors.forename: Maria Cecília B V
authors.initials: MC
authors.lastname: de Souza
authors.forename: Vitor F
authors.initials: VF
authors.lastname: Ferreira
authors.forename: Eliezer J
authors.initials: EJ
authors.lastname: Barreiro
mesh_terms: D000818:Animals; D005260:Female; D006835:Hydrazones / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D007249:Inflammation / Q000188:drug therapy; D008297:Male; D010974:Platelet Aggregation / Q000187:drug effects / Q000502:physiology; D010975:Platelet Aggregation Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D011817:Rabbits; D051381:Rats; D014230:Triazoles / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use
chemical_list: D006835:Hydrazones; D010975:Platelet Aggregation Inhibitors; D014230:Triazoles