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.
A series of substituted 2,3-dihydrothiazolo[2,3-a]isoindol-5(9bH)-ones and related compounds 1-73 were synthesized and evaluated for their ability to inhibit reverse transcriptase (RT) of the human immune deficiency virus 1 (HIV-1) and replication of HIV-1 in MT2 cells. The antiviral activity of these compounds depends on the stereoselective configuration of the substituent in position 9b. Structure-activity studies were done within these series of compounds to determine the optimum substituents for antiviral activity. The most potent inhibitors were found in the class of 2,3-dihydrothiazolo[2,3-a]isoindol-5(9bH)-ones bearing a phenyl ring system in position 9b optionally substituted with one or two methyl groups or a chlorine atom in position 8. The most active analogues (R)-(+)-1, (R)-(+)-6, (R)-(+)-13, (R)-(+)-26, and (R)-(+)-53 inhibit the HIV-1 RT with an IC50 between 16 and 300 nM and an IC50 between 10 and 392 nM in MT2 cells, respectively.
A series of substituted 2-pyridyl-6,7-dihydro-3H,5H-pyrrolo[2,3-f]benzimidazol-6-ones 1-24 were synthesized and evaluated for positive inotropic activity. In rats, cats, and dogs most of these tricyclic heterocycles produced a dose-related increase in myocardial contractility with little effect on heart rate and blood pressure. The increase in contractility was not mediated via stimulation of beta-adrenergic receptors. Compound 1 (BM 14.478) was more potent than milrinone (25) and enoximone when administered intravenously to rats, cats, and dogs. After oral administration of 1 mg/kg, compound 1, milrinone, and pimobendan were equipotent. However, only 1 and pimobendan were still active after 6 h. The structural requirements necessary for optimal cardiotonic activity within this novel class of heterocycles were investigated.
The protonation of aroyl azides in superacidic media at low temperature (-78 "C) occurs exclusively on the carbonyl oxygen leading to a-azidocarboxonium ions 2a-f. The 'H, 13C, and 15N NMR spectra of these ions indicate significant charge delocalization into the aryl ring as well as into the azido group. Upon warming up the solution these ions were, irreversibly, converted into benzoyl cations by loss of hydrozoic acid which was observed as protonated species.
Azidocarboxonium-Ionen l)Aroylazide werden in supersaurem Medium bei tiefer Temperatur ( -78 "C) ausschliefllich am Carbonylsauerstoffatom protoniert, was zu den a-Azidocarboxonium-Ionen 2a -f fiihrt. The protonation or complexation of the a-nitrogen as the first step in the Curtius rearrangement of aroyl azides catalyzed by a variety of Lewis and protic acids was suggested by Newman et aL3). Subsequently Fahr et al.4) were able to isolate BF3-complexes of aroyl azides at -60°C. Their infrared investigation showed an unchanged azide absorption, whereas the frequency of the carbonyl absorption was lowered to 1645 -1667 cm-'. Based on this observation the authors suggested, that the Lewis acid attacks on oxygen. Similar results were obtained in the case of azid~formates~) and azidoformamidinium salts6).
Results and DiscussionWe now wish to report the formation of a-azidocarboxonium ions by N M R spectroscopy via a direct protonation of acyl azides in superacidic media. The NMR data of the precursor azides l a -f and of the a-azidocarboxonium ions 2a -f are summarized in Tables 1 and 2. The effectiveness of the mesomeric contribution of the aryl ring was examined by the comparison between chemical shift differences of the precursors and of the a-azidocarboxonium ions. Table 3 contains the differences (A613C and A815N) of the 13C and 15N NMR chemical shifts. Analysis of the data obtained from 13C study, presence of an OH resonance and the absence of "N -H coupling was an evidence for the formation of a-azidocarboxonium ions via the protonation of acyl azides. These ions have a remarkable stability and could be kept in SO2 at -10°C for several hours 0 Verlag
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