Synthesis and biological evaluation of some 4‐(isoxazolinyl or 1,2,4‐oxadiazolyl) coumarins

Abstract

Reaction of compound 3 with nitrile oxide 4a affords compounds 5a and 6 in 73% and 3% yield respectively, while reaction of 3 with 4b affords only compound 5b (85%). Reactions of compound 8 with the nitrile oxides 4a,b result in compounds 9a,b. The compound 10, prepared from 1 and O‐methylhydroxylamine, reacts with nitrile oxide 4b to give the oxadiazole derivative 12. The above referred coumarins are screened for antiinflammatory activity in vivo using the carrageenin rat paw edema and in vitro through their antiproteolytic activity and their ability to inhibit β‐glucuronidase and 12‐Lipoxygenase.

Oxadiazoles

“…A widely exploited route to 4,5-dihydro-1,2,4-oxadiazoles is the 1,3-dipolar cycloaddition of nitrile oxides to azomethines [120,235].…”

A convenient synthesis of chiral 1,2,4-oxadiazoles from N-protected (α-aminoacyl)benzotriazoles

“…1 Numerous 1,2,4-oxadiazoles have been suggested as potential agonists for cortical muscarinic, 1c,2 benzodiazepine, 3 and 5-HT 1D (5-hydroxytryptamine) receptors, 4 and as antagonists for 5-HT 3 , 5 or histamine H 3 receptors. 6 They show activity as antirhinoviral agents, 1b growth hormone secretagogues, 7 anti-inflammatory agents, 8 and antitumor agents. 9 They also inhibit the SH2 domain of tyrosine kinase, 10 monoamine oxidase, 11 human nuetrophil elastase, 12 and human DNA topoisomerases.…”

tert-Butyl 4-{5-[3-(trifluoromethoxy)phenyl]-1,2,4-oxadiazol-3-yl}piperazine-1-carboxylate

“…For the synthesis and biological activity of 1,2,4-oxadiazoles, see: Chimirri et al (1996); Nicolaides et al (1998); Kemnitzer et al (2009).…”

“…They have been described as bio-isosteres for amides and esters. Due to increased hydrolytic and metabolic stabilities of the oxadiazole ring, improved pharmacokinetic and in vivo performance are often observed, which makes these heterocycles an important structural moiety for the pharmaceutical industry (Nicolaides et al, 1998). As a consequence of these, oxadiazoles have often been the target of numerous drug discovery programs as anti-inflammatory agents, anti-tumor agents, potential anticancer agents, Histamine H3 receptor antagonists as potent inhibitors of MIF biological function, and bell-tryptase inhibitors, In addition to these, 1,2,4-oxadiazoles are widely used as hydrolysis resisting amide bioisosteres in the development of peptidomimetics (Kemnitzer et al,2009).…”