Exploration of piperidine-4-yl-aminopyrimidines as HIV-1 reverse transcriptase inhibitors. N-Phenyl derivatives with broad potency against resistant mutant viruses.
ABSTRACT Further investigation of the recently reported piperidine-4-yl-aminopyrimidine class of non-nucleoside reverse transcriptase inhibitors (NNRTIs) has been carried out. Thus, preparation of a series of N-phenyl piperidine analogs resulted in the identification of 3-carboxamides as a particularly active series. Analogs such as 28 and 40 are very potent versus wild-type HIV-1 and a broad range of NNRTI-resistant mutant viruses. Synthesis, structure-activity relationship (SAR), clearance data, and crystallographic evidence for the binding motif are discussed.
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ABSTRACT: A range of novel 4-amino-6-arylpyrimidines has been prepared under mild conditions by an electrochemical reductive cross-coupling between 4-amino-6-chloro-pyrimidines and functionalized aryl halides. The process, which employs a sacrificial iron anode in conjunction with a nickel(II) catalyst, allows the formation of coupling products in moderate to high yields.Molecules 01/2011; 16(7):5550-60. · 2.43 Impact Factor
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ABSTRACT: BACKGROUND: The discovery of clinically relevant inhibitors of HIV-RT for antiviral therapy has proven to be a challenging task. To identify novel and potent HIV-RT inhibitors the quantitative structure-activity relationship (QSAR) approach became very useful and largely widespread technique for ligand based drug design. METHODS: We perform the two- and three-dimensional (2D and 3D) QSAR studies of a series of 1,2,3-Thiadiazole thioacetanilides Analogues to elucidate the structural properties required for HIV-RT inhibitory activity. RESULTS: The 2D-QSAR studies were performed using multiple linear regression method (MLR), giving r2 = 0.97 and q2 = 0.94. The 3D-QSAR studies were performed using the stepwise variable selection k-nearest neighbor molecular field analysis approach; a leave-one-out cross-validated correlation coefficient q2=0.89 and a non-cross-validated correlation coefficient r2=0.97 were obtained. Docking analysis suggests the new series have comparable binding affinity with the standard compounds. CONCLUSIONS: This approach showed that hydrophobic & electrostatic effects dominantly determine binding affinities which will further useful for development of new NNRTIs.Organic and medicinal chemistry letters. 06/2012; 2(1):22.
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ABSTRACT: A series of novel piperidinylamino-diarylpyrimidine (pDAPY) derivatives with dual structural conformations was designed through a molecular hybridization strategy and expected to bind into the non-nucleoside inhibitor binding pocket (NNIBP) of HIV-1 RT in a flexible manner. A cell-based antiviral screening assay showed that some compounds were active against both wild-type and drug-resistant mutant virus strains (K103N+Y181C RT) of HIV-1 (compound 10b3 with EC50=0.047 and 4.6μM, selectivity index=2145 and 22, respectively). Molecular simulation studies indicated that compound 10b3 could maintain the key hydrophobic interaction and hydrogen bonds with the NNIBP of two RT/ligand complexes. In particular, it could simultaneously occupy the protein/solvent interface and the entrance channel. Exploring these hybrid molecules with dual binding conformations might provide optional chemical scaffolds as novel HIV-1 reverse transcriptase inhibitors (HIV-1 NNRTIs).Bioorganic & medicinal chemistry letters 11/2013; · 2.65 Impact Factor