Synthesis and 5-Lipoxygenase Inhibitory Activities of Some Novel 2-Substituted 5-Benzofuran Hydroxamic Acids

Abstract

A series of 2-substituted benzofuran hydroxyamic acids were synthesized as rigid analogs of simple (benzyloxy)phenyl hydroxamates, evaluated for their in vitro and in vivo 5-lipoxygenase activity and found to be potent inhibitors of the enzyme. Substituents which enhanced lipophilicity near the 2-position of the benzofuran nucleus increased inhibitor potency but reduced oral activity. Incorporation of small polar substituents such as methoxymethylene, hydroxymethylene, and amino (urea) on the acyl group led to more consistent oral activity. The most potent inhibitors of this series in vitro were N-hydroxy-N-[1-(2-phenyl-5-benzofuranyl)-ethyl]furancarboxamide (12) and methyl 5-[N-hydroxy-N-[1-(2-(3,4,5-trimethoxyphenyl)-5-benzofuranyl]ethyl]-5- oxopentanoate (17), both with IC50 values of 40 nM, and in vivo the most potent compound was N-hydroxy-N-[1-(2-phenyl-5-benzofuranyl)ethyl]urea, 20, with an ED50 = 10.3 mg/kg.

Hydroxamic Acids as Pharmacological Agents

“…2-position of the benzofuran nucleus showed increased inhibitory potency as in the most active compound (55 , Table VII) [127].…”

Transition Metal‐Catalyzed Synthesis of Fused Five‐Membered Aromatic Heterocycles

“…Ohemeng [118] and Scammells [119] effectively employed the first catalytic system in the synthesis of biologically active benzofuran derivatives, whereas Nilsson succeeded in the assembly of OH X X = Br, I isocoumestan 4 from o-iodophenol 3 and ethyl propiolate using the second catalyst (vide supra, Scheme 9.1) [78].…”

Palladium‐Catalyzed Suzuki Coupling with Terminal Alkynes – Application to the Synthesis of 2,3‐Disubstituted Benzo[b]furans

“…were dissolved in dimethoxyethane (10 mL) and stirred for 10 min at room temperature. To the lithiated alkynylborate were successively added anhydrous tetrahydrofuran (3 mL) and the solution of Pd(PPh 3 ) 4 and aryl halide via cannula. The cannula and the flask were rinsed with dimethoxyethane (2 × 5 mL).…”

“…[1] Recently there has been a growing interest in developing general and versatile synthetic methods for the synthesis of benzofuran derivatives because of their activities as anti-tumor agents, [2] as ligands of the adenosine A1 receptor, [3] as inhibitors of 5-lipoxygenase, as antagonists of angiotensin II receptors [4] or as blood coagulation factor Xa inhibitors. [5] Some 2-arylbenzofuran derivatives are potent calcium blockers [6] while others show very good fungicidal activity in vitro and in vivo.…”