RESUMEN
We previously identified two small molecules targeting the HIV-1 gp41, N-(4-carboxy-3-hydroxy)phenyl-2,5-dimethylpyrrole 12 (NB-2) and N-(3-carboxy-4-chloro)phenylpyrrole 13 (NB-64), that inhibit HIV-1 infection at low micromolar levels. On the basis of molecular docking analysis, we designed a series of 2-aryl 5-(4-oxo-3-phenethyl-2-thioxothiazolidinylidenemethyl)furans. Compared with 12 and 13, these compounds have bigger molecular size (437-515 Da) and could occupy more space in the deep hydrophobic pocket on the gp41 NHR trimer. Fifteen 2-aryl 5-(4-oxo-3-phenethyl-2-thioxothiazolidinylidenemethyl)furans (11a-o) were synthesized by Suzuki-Miyaura cross-coupling followed by a Knoevenagel condensation and tested for their anti-HIV-1 activity and cytotoxicity on MT-2 cells. We found that all 15 compounds had improved anti-HIV-1 activity and 3 of them (11a, 11b, and 11d) exhibited inhibitory activity against replication of HIV-1(IIIB) and 94UG103 at <100 nM range, more than 20-fold more potent than 12 and 13, suggesting that these compounds can serve as leads for development of novel small molecule HIV fusion inhibitors.
Asunto(s)
Fármacos Anti-VIH/química , Fármacos Anti-VIH/farmacología , Furanos/química , Furanos/farmacología , VIH-1/efectos de los fármacos , VIH-1/fisiología , Internalización del Virus/efectos de los fármacos , Fármacos Anti-VIH/síntesis química , Fármacos Anti-VIH/metabolismo , Línea Celular , Diseño de Fármacos , Furanos/síntesis química , Furanos/metabolismo , Proteína gp41 de Envoltorio del VIH/química , Proteína gp41 de Envoltorio del VIH/metabolismo , Modelos Moleculares , Peso Molecular , Conformación Proteica , Relación Estructura-ActividadRESUMEN
[Structure: see text]. Reactions of readily available N-(alkyl-, aryl-, and heteroarylsulfonyl)benzotriazoles 3a-h with diverse nitriles, reactive heteroaromatics, alkylheteroaromatics, sulfones, and esters produced alpha-cyanoalkyl sulfones 5a-i, sulfonylheteroaromatics 7a-e, alpha-(sulfonylalkyl)heterocycles 9a-f, alpha-sulfonylalkyl sulfones 11a-g, and esters of alpha-sulfonyl acids 14a-c, respectively, in synthetically useful to excellent yields. The results represent the first examples of the successful application of sulfonylazoles for C-sulfonylation.
Asunto(s)
Sulfonas/química , Sulfonas/síntesis química , Ácidos Sulfónicos/química , Triazoles/química , Triazoles/síntesis químicaRESUMEN
Nitration of pyridines 1a-o with nitric acid in trifluoroacetic anhydride, gave the corresponding 3-nitropyridines 6a-n in yields of 10-83%.
RESUMEN
Molecules were prepared with substituted nitrobenzyl groups covalently bonded to N-(4-hydroxy-3-methoxybenzyl)acetamide (2) by ether or carbonate linkages. These compounds decomposed under irradiation at 363 nm. Those with carbonate linkages decomposed at slower rates than those with ether linkages. Molecules with dimethoxy-substituted benzyl groups decomposed more slowly than monomethoxy-substituted benzyl groups due to the electronic characteristics of the benzylic carbon.
Asunto(s)
Capsaicina/química , Modelos Químicos , Capsaicina/síntesis química , Espectroscopía de Resonancia Magnética , FotoquímicaRESUMEN
3,4-Dihydro-2H-1,3,5-thiadiazines substituted at the 3 and 6 positions were synthesized by treatment of N-substituted N,N-bis(1H-1,2,3-benzotriazol-1-ylmethyl)-amines with thioamides and zinc bromide in dry CH(2)Cl(2) at room temperature for 48-60 h in 48-80% yields.