Halogenated, alkylated and new types of imidazolidine, pyrrolidine, imidazotriazine and thienoimidazole derivatives with biological and antitumor activities

Abstract

New types of halogenated, alkylated and (bis)cyanothio-formamides were prepared and reacted with iso(thio)cyanates, aldehydes and dibenzylideneacetone to produce (bis)imidazolidineimino(di)thiones and (oxazolidine and bispyrrolidine)iminothiones, respectively. Imidazolidineiminothiones were reacted with H 2 S/TEA to give thiohydantoin which reacted with p-chlorobenzaldehyde to achieve the corresponding thienoimidazole derivative. Most of the synthesized products exhibited antibacterial, antifungal and antitumor activities.

Synthesis and Biological Evaluation of Bis‐Imidazolidineiminothiones: A Comparative Study

“…Thus, one equivalent of commercial hexamethylene diisocyanate ( 5 ) was reacted with two equimolar amounts of cyanothioformanilides 1a – g containing various aromatic substituents ( p ‐tolyl, p ‐methoxyphenyl, p ‐chlorophenyl, p ‐bromophenyl, p ‐iodophenyl, and 3,5‐dichlorophenyl) in ether, followed by the addition of a few drops of triethylamine as a catalyst to furnish the corresponding 3,3′‐(hexane‐1,6‐diyl)bis(1‐aryl‐4‐imino‐5‐thioxoimidazolidin‐2‐ones 6a – g as shown in Scheme . Arylcyanothioformanilides 1a – g were prepared by either treating an ethanolic solution of the requisite commercial arylisothiocyanate with an aqueous solution of KCN according to literature protocols or through the preparation of dithiocarbamates from aromatic amines, followed by conversion to the corresponding isothiocyanates, and a subsequent cyanation to afford the desired aryl cyanothioformanilides. The annulation reaction proceeded smoothly and cleanly by attack of the nitrogen atom of the arylcyanothioformanilide onto the isocyanate carbons of hexamethylene diisocyanate, where the ensuing ring closing step proceeded by attack of the resulting nitrogen anion onto the electrophilic nitrile group.…”

“…For the preparation of the known cyanothioformanilides 1a – g , see . Also see and references therein.…”

“…Interestingly, aromatic cyanothioformanilides are themselves bioactive and have been reported to exhibit a wide spectrum of bioactivity . Several classical methods as well as more recent eco‐friendly protocols have been reported in the literature for the preparation of such compounds.…”

“…N ‐Arylcyanothioformanilides are ambident nucleophiles and may react via the sulfur or nitrogen atom , with the nitrile group serving as an electrophilic tether that may participate in subsequent transformations. These inherent features have been employed to design several “one‐pot” annulation reactions to produce various heterocyclic cores .…”

“…We have recently described the preparation of imidazolidineiminothiones ( 3 ) and derivatives thereof and reported a detailed investigation of their in vitro biological activities. These were constructed in one step from N ‐arylcyanothioformanilides ( 1 ) via a heterocyclic ring closing reaction with various aromatic isocyanates ( 2 ) (Scheme ).…”