Synthesis and Preliminary Evaluation of N-Oxide Derivatives for the Prevention of Atherothrombotic Events

Abstract

Thrombosis is the main outcome of many cardiovascular diseases. Current treatments to prevent thrombotic events involve the long-term use of antiplatelet drugs. However, this therapy has several limitations, thereby justifying the development of new drugs. A series of N-oxide derivatives (furoxan and benzofuroxan) were synthesized and characterized as potential antiplatelet/antithrombotic compounds. All compounds (3a,b, 4a,b, 8a,b, 9a,b, 13a,b and 14a,b) inhibited platelet aggregation induced by adenosine-5-diphosphate, collagen, and arachidonic acid. All compounds protected mice from pulmonary thromboembolism induced by a mixture of collagen and epinephrine; however, benzofuroxan derivatives (13a,b and 14a,b) were the most active compounds, reducing thromboembolic events by up to 80%. N-oxide derivative 14a did not induce genotoxicity in vivo. In conclusion, 14a has emerged as a new antiplatelet/antithrombotic prototype useful for the prevention of atherothrombotic events.

Molecular Hybridization Tools in the Development of Furoxan‐Based NO‐Donor Prodrugs

“…Target hybrids 32 a – d are weak NO donors and show good antiplatelet activity induced by three agonists (ADP, collagen, and arachidonic acid). Interestingly, the anti‐aggregation properties of hybrids 32 a – d are significantly higher than those of the parent hydrazones 27 f , g and 28 f , g …”

“… Synthesis of furoxanylhydrazone hybrids . Reagents and conditions : a) RCONHNH 2 , HCl or AcOH (cat.…”

“…The combination of af uroxanyl moiety with an N-acyl hydrazone subunit resulted in the development of novel antibacterial and antiparasitic drug candidates.Awide variety of hydrazones 27 a-r and 28 a-r can be easily obtained by interaction of readily availablef uroxancarbaldehydes 26 a,b with appropriate (het)aroylhydrazines, predominantly with high yields (Scheme9). [32][33][34][35] The pharmacological activities of the synthesized hybrids 27 a-r and 28 a-r are rathere ncouraging. Hydrazones 27 d and 28 d,w hich contain a4 -nitrophenyl moiety,w ere found to be activea gainst Trypanosoma cruzi (in amastigote form) responsible for Chagas disease.…”

“…[33] Hydrazones 27 f,g and 28 f,g,i ncorporating ap henol moiety,w ere further functionalized through esterification with acetylsalicylica cid;h owever,y ields of the final compounds 32 a-d were rather moderate Scheme9.Synthesis of furoxanylhydrazone hybrids. [32][33][34][35] Reagents and conditions: a) RCONHNH 2 ,H Cl or AcOH (cat. ), EtOH, reflux,6-98 %.…”

“…Interestingly,t he anti-aggregation properties of hybrids 32 a-d are significantly highert han those of the parent hydrazones 27 f,g and 28 f,g. [34] The positions of the hydrazone and phenol subunits can be swapped in order to obtain another type of hybrid:c ompounds 33 a-f and 34 a-c (Scheme 13). The synthesis of target compounds 33 a-f and 34 ac was achieved using at andem methodology involving nucleophilic substitution of an itro or phenylsulfonyl group in the initial furoxans 11, 15 b,c under the action of phenolic aldehydes with subsequentc ondensation of the formyl group with isonicotinic hydrazide.…”