The structural features of a new class of non-nucleoside HIV-1 reverse transcriptase inhibitors (3) are presented. Comparison of the structural and electronic properties with those of TIBO (1) and Nevirapine (2) yields a common three-dimensional model. This model permits the improvement of the lead compound 3 by chemical modification (5,6). Additionally, two new types of inhibitors (4, 7) with similar biological activity can be derived from this model. The structure of the new compounds, including their absolute configuration, are determined by X-ray crystallography.
The hexadentate bispidine-based ligand 2,4-bis(2-pyridyl)-3,7-bis(2-methylenepyridine)-3,7-diazabicyclo[3.3.1]nonane-9-on-1,5-bis(carbonic acid methyl ester), L(6m), with four pyridine and two tertiary amine donors, based on a very rigid diazaadamantane-derived backbone, is coordinated to a range of metal ions. On the basis of experimental and computed structural data, the ligand is predicted to form very stable complexes. Force field calculations indicate that short metal-donor distances lead to a buildup of strain in the ligand; that is, the coordination of large metal ions is preferred. This is confirmed by experimentally determined stability constants, which indicate that, in general, stabilities comparable to those with macrocyclic ligands are obtained with the relative order Cu(2+) > Zn(2+) >> Ni(2+) < Co(2+), which is not the typical Irving-Williams behavior. The preference for large M-N distances also emerges from relatively high redox potentials (the higher oxidation states, that is, the smaller metal ions, are destabilized) and from relatively weak ligand fields (dd-transition, high-spin electronic ground states). The potentiometric titrations confirm the efficient encapsulation of the metal ions since only 1:1 complexes are observed, and, over a large pH range, ML is generally the only species present in solution.
The copper(I) compounds [Cu(dppe)2]X [X = BF4−, I−; dppe = 1,2‐bis(diphenylphosphanyl)ethane], [Cu(dppp)2]X [X = BF4−,I−; dppp = 1,3‐bis(diphenylphosphanyl)propane], [Cu2(dppe)3I2], and [Cu2(dppe)2I2] have been prepared and their structural properties in solution and in the solid state have been determined. 1H‐, 13C‐, and 31P‐NMR spectra in solution [variable temperature and anion (I−) concentrations] and analyses of solids (mass spectra, elemental analyses, and CPMAS 31P‐NMR spectra) are interpreted with equilibria in solution that involve two mono‐ and two dinuclear species. The structures of [Cu(dppe)2]ClO4, [Cu(dppp)2]BF4, and [Cu2(dppe)3I2] · 2 CHCl3 have been analyzed by X‐ray crystallography. In all three structures the copper(I) center adopts a distorted tetrahedral geometry.
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