Thiourea bioisosteres

The frequently observed bioisosteric relation of benzene and thiophene applies to the clonidine series as well. Reaction of the thiophenyl thiourea (85-1), in which the amine group is flanked by substituents as in the prototype, with methyl iodide and a base gives the corresponding methyl thioether (85-2). Treatment of that intermediate with ethylene diamine leads to the formation of an imidazoline ring and the antihypertensive agent, tiamenidine (85-3) [90], shown as its imino tautomer. 

The finding that metiamide and cimetidine are both good H2 antagonists of similar activity shows that the cyanoguanidine group is a good bioisostere for the thiourea group. 

In a smdy undertaken on antagonists of the dihydropyridine neuropeptide Yi receptor, common bioisosteres such as thiourea and cyanoguanidine were examinated as urea replacement (Figure 15.37) and also more uncommon derivatives like squaric acid and thiadiazole oxide. 

In the histaminic H2 receptor antagonist series, the classical urea-thiourea-guanidine progression was successfully completed by the use of the V-nitro and V-cyanoguanidines and, later on, by l,l-diamino-2-nitroethylene groups (Fig. 13.19). Cyano amidines and carbamoyl amidines were also used, and structure-activity relationship patterns were rationalized in terms of dipole moment orientation of related bioisosteric groups. ... 

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