Drug design of new antitubercular agents: 1,3-dipolar cycloaddition reaction of arylnitriloxides and 3-para-methoxy-benzylidene-isochroman-4-ones

Abstract

Five new 3',4'-substituted-spiro[isochromene-3,5'-isoxazolin]-4(1H)-ones 7-11 have been prepared in the reaction of p-R-benzadoxime 2-6 with 3-para-methoxy-benzylidene-isochroman-4-one 1. The reaction occurs by a 1,3-dipolar cycloaddition mechanism which leads to the regiospecific formation of various spiro-isoxazolines 7-11. It is concluded that rigid (O 1'group may be responsible for the biological activity observed in antitubercular test with these hyper inter-organised spiro-isoxazoline derivatives. However, subtle alteration by addition of a substituted aryl groups affecting the charge distribution of the terminal heteroatom O 1' confers significant improvements in biological effects.

Synthesis of new spiroheterocycles-fused isoxazoline from 2-arylidenes-3-phenyl-1-indanones through a regio-and diastereospecific 1,3-dipolar cycloaddition

“…The 1,3-dipolar cycloaddition reaction of alkynes/alkenes with nitrile oxides, respectively, constitutes a versatile tool to access isoxazole and isoxazoline heterocycles [23][24][25] . In this context, and in continuation of our ongoing research devoted to synthesis heterocyclic compounds with promising biological and pharmacological activities via 1,3dipolar cycloaddition across dipolarophiles with exocyclic double bond with several 1,3-dipoles 16,20 . We describe a reaction between arylnitrile oxides precursors (arylaldoximes) and arylidenes-indanone derivatives in one pot, to give the desired spiroisoxazolines 3 (Scheme 1).…”

“…In addition, the spiroisoxazoline scaffold forms an integral part of many beneficial biologically active compounds. Indeed, spiroisoxazolines exhibit an extensive array of biological and pharmacological activities such as antiviral 13 , anticancer 14,17,18 , antimalarial 15 , antituberculosis 16 , antibacterial 17,19 and antiparasitic 20 .…”

“…Spiroisoxazolines synthesized in our laboratory in 2005 have been patented for their antituberculosis and anti-HIV properties 21,22 . Since then, we have been further developing these highly promising molecules 16,20 .…”

Crystal structure of 4-(4-methoxyphenyl)-4′,4′-dimethyl-3-p-tolyl-3′,4′-dihydro-1′H,3H-spiro[isoxazole-5,2′-naphthalen]-1′-one

“…For general background to 1,3-dipolar cycloaddition reactions, see: Al Houari et al (2008. For the structures of related compounds, see: Akhazzane et al (2010Akhazzane et al ( , 2011; Mahfoud et al (2015).…”

“…In the context of our research concerning the approach of dipole-dipolarophile in 1,3-dipolar cycloaddition, we have already studied the case where the dipole is an arylnitriloxide and the dipolarophiles are 2-arylidenes of tetralone (systematic name: 3,4-dihydronaphthalen-1-one) substituted by an anisopropyl group in position 4 (Al Houari et al, 2008;Al Houari et al, 2010). We have shown that the ring closure reaction is highly regiselective and also highly diastereoselective.…”