RESUMEN
AIM: The only small molecule drugs currently available for treatment of influenza A virus (IAV) are M2 ion channel blockers and sialidase inhibitors. The prototype thiazolide, nitazoxanide, has successfully completed Phase III clinical trials against acute uncomplicated influenza. RESULTS: We report the activity of seventeen thiazolide analogs against A/PuertoRico/8/1934(H1N1), a laboratory-adapted strain of the H1N1 subtype of IAV, in a cell culture-based assay. A total of eight analogs showed IC50s in the range of 0.14-5.0 µM. Additionally a quantitative structure-property relationship study showed high correlation between experimental and predicted activity based on a molecular descriptor set. CONCLUSION: A range of thiazolides show useful activity against an H1N1 strain of IAV. Further evaluation of these molecules as potential new small molecule therapies is justified.
Asunto(s)
Antivirales/química , Antivirales/farmacología , Subtipo H1N1 del Virus de la Influenza A/efectos de los fármacos , Tiazoles/química , Tiazoles/farmacología , Descubrimiento de Drogas , Humanos , Virus de la Influenza A/efectos de los fármacos , Gripe Humana/tratamiento farmacológico , NitrocompuestosRESUMEN
We report the activities of a number of thiazolides [2-hydroxyaroyl-N-(thiazol-2-yl)amides] against hepatitis C virus (HCV) genotypes IA and IB, using replicon assays. The structure-activity relationships (SARs) of thiazolides against HCV are less predictable than against hepatitis B virus (HBV), though an electron-withdrawing group at C(5') generally correlates with potency. Among the related salicyloylanilides, the m-fluorophenyl analogue was most promising; niclosamide and close analogues suffered from very low solubility and bioavailability. Nitazoxanide (NTZ) 1 has performed well in clinical trials against HCV. We show here that the 5'-Cl analogue 4 has closely comparable in vitro activity and a good cell safety index. By use of support vector analysis, a quantitative structure-activity relationship (QSAR) model was obtained, showing good predictive models for cell safety. We conclude by updating the mode of action of the thiazolides and explain the candidate selection that has led to compound 4 entering preclinical development.
Asunto(s)
Amidas/síntesis química , Antivirales/síntesis química , Hepacivirus/efectos de los fármacos , Tiazoles/síntesis química , Amidas/química , Amidas/farmacología , Antivirales/química , Antivirales/farmacología , Línea Celular , Hepacivirus/genética , Hepacivirus/fisiología , Humanos , Relación Estructura-Actividad Cuantitativa , Tiazoles/química , Tiazoles/farmacología , Replicación Viral/efectos de los fármacosRESUMEN
We report the syntheses and activities of a wide range of thiazolides [viz., 2-hydroxyaroyl-N-(thiazol-2-yl)amides] against hepatitis B virus replication, with QSAR analysis of our results. The prototypical thiazolide, nitazoxanide [2-hydroxybenzoyl-N-(5-nitrothiazol-2-yl)amide, NTZ] 1 is a broad spectrum antiinfective agent effective against anaerobic bacteria, viruses, and parasites. By contrast, 2-hydroxybenzoyl-N-(5-chlorothiazol-2-yl)amide 3 is a novel, potent, and selective inhibitor of hepatitis B replication (EC(50) = 0.33 µm) but is inactive against anaerobes. Several 4'- and 5'-substituted thiazolides show good activity against HBV; by contrast, some related salicyloylanilides show a narrower spectrum of activity. The ADME properties of 3 are similar to 1; viz., the O-acetate is an effective prodrug, and the O-aryl glucuronide is a major metabolite. The QSAR study shows a good correlation of observed EC(90) for intracellular virions with thiazolide structural parameters. Finally we discuss the mechanism of action of thiazolides in relation to the present results.
Asunto(s)
Amidas/síntesis química , Antivirales/síntesis química , Virus de la Hepatitis B/efectos de los fármacos , Profármacos/síntesis química , Salicilamidas/síntesis química , Tiazoles/síntesis química , Amidas/farmacocinética , Amidas/farmacología , Animales , Antivirales/farmacocinética , Antivirales/farmacología , Perros , Glucurónidos/síntesis química , Glucurónidos/farmacocinética , Glucurónidos/farmacología , Células Hep G2 , Virus de la Hepatitis B/fisiología , Humanos , Técnicas In Vitro , Profármacos/farmacocinética , Profármacos/farmacología , Relación Estructura-Actividad Cuantitativa , Ratas , Salicilamidas/farmacocinética , Salicilamidas/farmacología , Tiazoles/farmacocinética , Tiazoles/farmacología , Virión/efectos de los fármacos , Virión/fisiología , Replicación ViralRESUMEN
A new approach to benzyne precursors has been developed that involves the [4+2] cycloaddition of trimethylsilyl alkynylboronates with 2-pyrones, followed by oxidation and trifluoromethylsulfonylation of the boronate moiety.
Asunto(s)
Derivados del Benceno/química , Ácidos Borónicos/química , Ciclización , Oxidación-Reducción , Pironas/químicaRESUMEN
We report the preparation and antiparasitic activity in vitro and in vivo of a series of isoflavone derivatives related to genistein. These analogues retain the 5,7-dihydroxyisoflavone core of genistein: direct genistein analogues (2-H isoflavones), 2-carboethoxy isoflavones, and the precursor deoxybenzoins were all evaluated. Excellent in vitro activity against Cryptosporidium parvum was observed for both classes of isoflavones in cell cultures, and the lead compound 19, RM6427, shows high in vivo efficacy against an experimental infection.
