title: Synthesis of N-benzyl- and N-phenyl-2-amino-4,5-dihydrothiazoles and thioureas and evaluation as modulators of the isoforms of nitric oxide synthase.
abstract: Inhibition of the isoforms of nitric oxide synthase (NOS) has important applications in therapy of several diseases, including cancer. Using 1400 W [N-(3-aminomethylbenzyl)acetamidine], thiocitrulline and N(delta)-(4,5-dihydrothiazol-2-yl)ornithine as lead compounds, series of N-benzyl- and N-phenyl-2-amino-4,5-dihydrothiazoles and thioureas were designed as inhibitors of NOS. Ring-substituted benzyl and phenyl isothiocyanates were synthesised by condensation of the corresponding amines with thiophosgene and addition of ammonia gave the corresponding thioureas in high yields. The substituted 2-amino-4,5-dihydrothiazoles were approached by two routes. Treatment of simple benzylamines with 2-methylthio-4,5-dihydrothiazole at 180 degrees C afforded the corresponding 2-benzylamino-4,5-dihydrothiazoles. For less nucleophilic amines and those carrying more thermally labile substituents, the 4,5-dihydrothiazoles were approached by acid-catalysed cyclisation of N-(2-hydroxyethyl)thioureas. This cyclisation was shown to proceed by an S(N)2-like process. Modest inhibitory activity was shown by most of the thioureas and 4,5-dihydrothiazoles, with N-(3-aminomethylphenyl)thiourea (IC(50)=13 microM vs rat neuronal NOS and IC(50)=23 microM vs rat inducible NOS) and 2-(3-aminomethylphenylamino)-4,5-dihydrothiazole (IC(50)=13 microM vs rat neuronal NOS and IC(50)=19 microM vs human inducible NOS) being the most potent. Several thioureas and 4,5-dihydrothiazoles were found to stimulate the activity of human inducible NOS in a time-dependent manner.
authors.affiliation: Department of Pharmacy & Pharmacology, University of Bath, Claverton Down, BA2 7AY, Bath, UK.
authors.forename: Claire L M
authors.initials: CL
authors.lastname: Goodyer
authors.forename: Edwin C
authors.initials: EC
authors.lastname: Chinje
authors.forename: Mohammed
authors.initials: M
authors.lastname: Jaffar
authors.forename: Ian J
authors.initials: IJ
authors.lastname: Stratford
authors.forename: Michael D
authors.initials: MD
authors.lastname: Threadgill
mesh_terms: D000818:Animals; D001665:Binding Sites; D002147:Calmodulin / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology; D005069:Evaluation Studies as Topic; D006801:Humans; D020128:Inhibitory Concentration 50; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors*; D020033:Protein Isoforms / Q000378:metabolism; D051381:Rats; D013329:Structure-Activity Relationship; D013844:Thiazoles / Q000138:chemical synthesis* / Q000494:pharmacology; D013890:Thiourea / Q000031:analogs & derivatives* / Q000494:pharmacology
chemical_list: D002147:Calmodulin; D004791:Enzyme Inhibitors; D020033:Protein Isoforms; D013844:Thiazoles; D019001:Nitric Oxide Synthase; D013890:Thiourea