The present invention is directed to novel catechol diether compounds, pharmaceutical compositions therefrom and methods for inhibiting reverse transcriptase and treating HIV infections, especially included drug resistant strains of HIV 1 and 2 and/or sec
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Page/Page column 49-50
(2013/04/25)
Computationally-guided optimization of a docking hit to yield catechol diethers as potent anti-HIV agents
A 5-μM docking hit has been optimized to an extraordinarily potent (55 pM) non-nucleoside inhibitor of HIV reverse transcriptase. Use of free energy perturbation (FEP) calculations to predict relative free energies of binding aided the optimizations by identifying optimal substitution patterns for phenyl rings and a linker. The most potent resultant catechol diethers feature terminal uracil and cyanovinylphenyl groups. A halogen bond with Pro95 likely contributes to the extreme potency of compound 42. In addition, several examples are provided illustrating failures of attempted grafting of a substructure from a very active compound onto a seemingly related scaffold to improve its activity. (Figure presented)
Bollini, Mariela,Domaoal, Robert A.,Thakur, Vinay V.,Gallardo-Macias, Ricardo,Spasov, Krasimir A.,Anderson, Karen S.,Jorgensen, William L.
p. 8582 - 8591
(2012/02/02)
1-[2-(2-Benzoyl- and 2-benzylphenoxy)ethyluracils as potent anti-HIV-1 agents
Non-nucleoside reverse transcriptase inhibitors (NNRTI) are key components in highly active antiretroviral therapy for treating HIV-1. Herein we present the synthesis for a series of N1-alkylated uracil derivatives bearing ω-(2-benzyl- and 2-benzoylphenoxy)alkyl substituents as novel NNRTIs. These compounds displayed anti-HIV activity similar to that of nevirapine and several of them exhibited activity against the K103N/Y181C RT mutant HIV-1 strain. Further evaluation revealed that the inhibitors were active against most nevirapine-resistant mono- and di-substituted RTs with the exception of the V106A RT. Thus, the candidate compounds can be regarded as potential lead compounds against the wild-type virus and drug-resistant forms.
Novikov, Mikhail S.,Ivanova, Olga N.,Ivanov, Alexander V.,Ozerov, Alexander A.,Valuev-Elliston, Vladimir T.,Temburnikar, Kartik,Gurskaya, Galina V.,Kochetkov, Sergey N.,Pannecouque, Christophe,Balzarini, Jan,Seley-Radtke, Katherine L.
experimental part
p. 5794 - 5802
(2011/11/04)
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