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Anti-HIV-1 NNRT agents: Acylamino Pyrryl Aryl Sulfones (APASs) as truncated analogues of tricyclic PBTDs

Silvestri R., De Martino G., Artico M., La Regina G., Ragno R., Loddo R., La Colla P., Marongiu M.E., La Colla M., Pani A., Medicinal Chemistry Research, 2002


Abstract:

Pyrryl Aryl Sulfones (PASs) bearing acylamino moieties at position 2 of the benzene ring were designed as truncated analogs of pyrrolo[1,2-b][1,2,5]benzothiadiazepine 5,5-dioxides (PBTDs). Acylamino-PASs (APASs) were synthesized by reacting 1-(2-amino-5-chlorobenzenesulfonyl)-2-ethoxycarbonyl-1H-pyrrole with alkanoyl, aroyl or benzenesulfonyl halides in the presence of pyridine or sodium hydrogen carbonate. Some of test compounds were achieved by treating 1-(2-bromoacetylamino-5-chlorobenzenesulfonyl)-2-ethoxycarbonyl-1H-pyrrole with appropriate amines, heterocycles or sodium thiomethoxide. Reaction of 1-(2-acetylamino-5-chlorobenzenesulfonyl)-1H-pyrrole with acetyl chloride in the presence of boron trifluoride ethyl etherate or aluminum chloride afforded the related 2- and 3-acetyl-1H-pyrrole isomers. The most potent derivatives 1- [2-(1-X-acetyl)amino-5-chlorobenzenesulfonyl]-2-ethoxycarbonyl-1H-pyrroles (X = CH3O, CH3S) were active at submicromolar concentrations, comparable with that of nevirapine. Various derivatives were as active as the related cyclic pyrrolobenzothiadiazepines (PBTDs). A binding mode investigation by molecular modeling and docking studies is reported for these novel NNRTIs. Furthermore, some information about the relation between hydrophobicity and anti-HIV activity were evaluated using calculated logP values.


Link to the article:

http://dx.doi.org/nan