Latent inhibitors. Part 6. Inhibition of dihydro-orotate dehydrogenase by substituted 5-benzylhydantoins

Abstract

A series of substituted 5benzyl-3-(1 -carboxy-2-phenylethyl) hydantoins was prepared by condensation of aromatic aldehydes with the corresponding 5-unsubstituted hydantoin followed by reduction of the intermediate benzylidene derivative. The compounds were assessed as inhibitors of dihydroorotate dehydrogenase from Clostridium oroticum. It was found that hydrophobic and electron-donating substituents in the phenyl ring of the benzyl group favoured binding and irreversible inhibition. The results for the series were correlated with standard substituent parameters from which a mechanism of inhibition was derived. This involved rapid deprotonation of the hydantoin at C-5 followed by ratedetermining removal of hydride, or its equivalent.Dihydro-orotate dehydrogenase (DHODase) is an enzyme in the biosynthetic pathway to pyrimidines and has been recognised as a potential candidate for inhibition in chemotherapy.* We have shown that dihydro-orotate dehydrogenase from CZostridium oroticum was inhibited by the parent member of the series, 5-benzyl-3-( 1 -carboxy-Zphenyl-ethy1)hydantoin t 5a in a time-dependent and irreversible manner.3 On the basis of the intrinsic chemical properties of the inhibitor and a computer-generated comparison of the structures of substrate and inhibitor, we proposed a mechanism in which the 5-benzyl group was oxidised by the enzyme to a benzylidene group; the product would have structure 4a and this would give rise to an a,a-unsaturated carbonyl compound to which the enzyme might be expected to add. The present work was designed to probe further the mechanism of this unexpected reaction and to obtain additional related compounds with potentially improved biological activity.Synthesis.-The previous synthesis starting from ( S ) -* Figures relate to the binary complex of enzyme plus inhibitor.Data are for the racemate, m.p. 187-188°C. bData are for the racemate, m.p. 196-198 "C.

Mechanochemical Preparation of 3,5-Disubstituted Hydantoins from Dipeptides and Unsymmetrical Ureas of Amino Acid Derivatives

“…1,3−5 They have been notably presented as inhibitors of dihydro-orotate dehydrogenase from Clostridium (Zymobacterium) oroticum for the potential treatment of parasitic diseases. 6,7 From the synthetic point of view, these structures have been often reported as byproducts in peptide synthesis. 8−11 However, their structural and biological interests have given rise to the development of several methodologies for their preparation.…”

“…The hydantoin core offers numerous possibilities of substitutions, allowing building a large diversity of potential structures. In particular, 5-substituted-3-(alkoxycarbonyl)­alkyl-hydantoin derivatives (Figure ) present a particular substitution pattern, which make them interesting peptidomimetics and bioactive compounds with antiepileptic, anticonvulsant, antiarrhythmic, or antibacterial properties. ,− They have been notably presented as inhibitors of dihydro-orotate dehydrogenase from Clostridium ( Zymobacterium ) oroticum for the potential treatment of parasitic diseases. , …”

“…The reaction of amino acid derivatives with isocyanates led to the formation of such hydantoins, after cyclization of the corresponding ureido derivatives in strong acidic conditions ,,, (Figure a). N -alkylation with halogeno acetates and their derivatives, ,,, and Michael addition reactions, allowed the introduction of the carboxyalkyl group at the N -3 position of hydantoins, with a particular interest in phenytoin derivatives ,− ,, (Figure b). Miscellaneous procedures reported the reaction between acetylenic diesters and isocyanides, or phosphates, in the presence of an hydantoin molecule (Figure b).…”

“…The second one describes the CDI activation of N -terminal moieties of dipeptides followed by cyclization (Scheme , method B). The disclosed methodology is a valid eco-friendly alternative (replacing the use of triphosgene) to prepare 5-benzyl-3-(methyloxycarbonyl)­benzyl hydantoin 2e (Table , entry 5), which the corresponding carboxylic acid is an antiparasite agent, inhibitor of dihydro-orodotase dehydrogenase from Clostridium ( Zymobacterium ) oroticum . , …”

Preparation and fungicidal activity of 5-substituted hydantoins and their 2-thio analogs

“…The data of 18 are given in Table I. Howie et al (1990) reported an efficient method for the preparation of 18, but we could not compare it with our method because the yields were absent. [44][45][46][47].…”