A versatile thiouronium-based solid-phase synthesis of 1,3,5-triazines.

A thiouronium-based solid-phase synthesis of a 1,3,5-triazine scaffold has been developed. The key feature of the synthesis is the use of a readily accessible solid-supported thiouronium salt as a primary precursor for the stepwise assembly of the 1,3,5-triazine substrate. The sulfur linker employed in the synthesis is stable under both acidic and basic conditions and is versatile enough to provide access to monocyclic, bicyclic, and spirocyclic compounds with the 1,3,5-triazine scaffold. By using this synthetic strategy, a representative set of 79 compounds containing the 1,3,5-triazine scaffold were prepared.

Traceless solid-phase synthesis of 6-amino- and 6-hydroxyimino-1,3,5-triazine-2,4-diones and 1,3,5-triazine-2,4,6-triones.

A traceless solid-phase synthesis of 6-amino- and 6-hydroxyimino-1,3,5-triazine-2,4-diones and 1,3,5-triazine-2,4,6-triones has been developed. The strategy comprises of linking a preformed N-carbamothioylcarbamate to bromomethyl resin to give a S-linked isothiourea, which then undergoes cyclization with isocynates to yield the resin-bound 1,3,5-triazine-2,4-diones. Subsequent cleavage was accomplished by either direct substitution with a suitable amine or by oxidative activation of the thioether functionality followed by nucleophilic substitution. Using this synthetic strategy, we prepared a representative set of 31 6-amino-1,3,5-triazine-2,4-diones, 10 6-hydroxyimino-1,3,5-triazine-2,4-diones, and 8 1,3,5-triazine-2,4,6-triones.

Synthesis and the biological evaluation of 2-benzenesulfonylalkyl-5-substituted-sulfanyl-[1,3,4]-oxadiazoles as potential anti-hepatitis B virus agents.

Current treatments for chronic hepatitis B virus (HBV) infection include the use of interferon-alpha and of nucleoside analogs lamivudine, adefovir and entecavir. However, the use of interferon-alpha has many side effects while that of nucleosidic inhibitors can lead to the emergence of resistant viruses. Hence, new drugs for the treatment of HBV infection are still highly desired. Oxadiazoles have been observed to exhibit antiviral activities against RNA viruses. In this study, a facile synthesis of 2-benzenesulfonylalkyl-5-substituted-sulfanyl-[1,3,4]-oxadiazoles is reported. The compounds were then evaluated for their anti-HBV activity. 1-[2-[5-(1-Benzenesulfonyl-propyl)-[1,3,4]oxadiazol-2-yl-sulfanyl]-ethyl]-4-(2-methoxy-phenyl)-piperazine (1i) was able to inhibit the expression of the viral antigens, HBsAg and HBeAg in a concentration-dependent manner with no cytotoxic effects and without any effects on the expression of viral transcripts. Concentration- and time-dependent reductions in virion production were also observed. The inhibition of virion production was comparable to that of lamivudine and EC(50) values of 1.63 and 2.96 microM were obtained for compound 1i and lamivudine, respectively. Thus, in addition to the antiviral effects on RNA viruses, oxadiazoles also have anti-HBV activities.

Traceless solid-phase synthesis of nitrogen-containing heterocycles and their biological evaluations as inhibitors of neuronal sodium channels.

The preparation of pyrimidine-2-thione, pyrimidine-2-one, pyrimidine, and benzo[b][1,4]diazepine derivatives using traceless solid-phase sulfone linker strategy is described. Key steps involved are (i) sulfinate S-alkylation, (ii) sulfone anion alkylation with an epoxide, (iii) gamma-hydroxyl sulfone --> gamma-ketosulfone oxidation, and (iv) traceless product release by a one-pot elimination-cyclization process. Elimination-cyclization was carried out under basic conditions with thiourea, methyl thiourea, methyl urea, guanidine hydrochloride, benzamidine hydrochloride and ortho-phenylene diamine. Twenty-three compounds were prepared, and 14 of them were evaluated by the Batrachotoxin (BTX) radioligand binding assay for their binding affinity to neuronal sodium channels. Compound 7c was found to be a potential neuronal sodium channels blocker.