The N-substituted Chiral Thiourea Derivatives, Synthesis And Biological Activity

Thioureas occupy important position in pesticide chemistry due to their strong biological activities; they possess antibacterial and antifungal activities and can act as herbicides and rodenticides. A number of researchers have successfully developed a series of thiourea compounds as fungicide (thiophamine), insecticide (chloromethiuron), acaricide (diafenthiuron), plant growth regulator (fup-henthiourea) in the last ten years. These compounds have been one of the focuses in chemical and biological research fields.In order to extend our research work of chiral thiourea as antiviral agent against tobacco mosaic virus (TMV), we designed and synthesized thirty novel chiral thiourea derivatives. Twenty-four N-aryl-N-substituted chiral thiourea compounds were prepared by the reaction of aryl isothiocyanates with chiral amine at room temperature. Three N-substituted chiral thiourea cocmpounds containing phosphonate group were synthesized by the reaction ofα-aminophosphonate with (R)-(1-isothiocyanatoethyl)-benzene at room temperature. Finally, one N-substituted chiral thiourea compound containing acyl group was prepared from amino acid and isothiocyanate through three step reactions. Two N-substituted chiral thiourea bearing acyl moiety were prepared from (S)-2-(tert-butoxycarbonylamino)-4-methylpentanoic acid, aryl amine and isothiocyanatobenzene. The structures of all compounds were verified by IR, ¹H NMR, ¹³C NMR and elemental analysis.The reaction conditions for the intermediate and some representative title compounds were studied. For the preparation of isothiocyanates, it was found that the one with ethyl chloroformate method gave higher yield and less by-products than that with phosphoryl trichloride. For the title compounds synthesis, it was found that ionic liquid can accelerate the reaction from 30 min to 5 min and improve the yield from 61.1～73.7% to 70.1～85.5%.Bioassay showed that all compounds exhibited certain antiviral activity against tobacco mosaic virus. Compound A₉ displayed good protection effect, in vivo curative effect against TMV with inhibitory rates of 57.0%, 55.0% at 500μg/mL respectively. Its protection activity and curative activity are higher than that of Ninnanmeisu.