Computer-Aided Molecular Modeling, Synthesis, and Biological Evaluation of 8-(Benzyloxy)-2-phenylpyrazolo[4,3-c]quinoline as a Novel Benzodiazepine Receptor Agonist Ligand

Abstract

Using computer-aided conformational analysis, based on molecular dynamics simulation, cluster analysis, and Monte Carlo techniques, we have designed and synthesized compounds in which a benzyloxy substituent has been incorporated into a series of pyrazoloquinoline benzodiazepine receptor (BZR) ligands. Earlier studies had shown that the benzyloxy group could act as part of the agonist pharmacophoric determinant in the beta-carboline ring system. Furthermore, the agonist beta-carboline had been correlated with a binding site orientation and volume fit for an agonist 6-phenylimidazobenzodiazepine carboxylate. The present study was undertaken to determine whether the benzyloxy substituent could be used as an agonist pharmacophoric descriptor for the phenylpyrazolo[4,3-c]quinolin-3-one BZR ligands. The results of a determination of GABA shift ratios for the synthetic ligands indicate that 8-(benzyloxy)-2-phenylpyrazolo[4,3-c]quinolin-3-one can be predicted to be an agonist at the BZR.

Quinolinonyl Non-Diketo Acid Derivatives as Inhibitors of HIV-1 Ribonuclease H and Polymerase Functions of Reverse Transcriptase

“…Condensation of ( E )-3-(4-aminophenyl)-1-phenylprop-2-en-1-one ( 6 ) with diethyl ethoxymethylenemalonate (EMME) gave intermediate 7 , which was submitted to thermal ring closure to give 8k (Gould–Jacobs reaction) . Derivatives 5a–c,e–i,k were obtained by alkylation in position 1 of the proper quinolinonyl derivative 8a–c,e–i − or 8k with p -fluorobenzyl bromide in the alkaline medium. The subsequent base-catalyzed hydrolysis of ester derivatives 5a–c,e–i,k afforded the corresponding acids 4a–c,e–i,k .…”

Structure-guided optimization of quinoline inhibitors of Plasmodium N-myristoyltransferase

“…The intermediate ethyl 6-(benzyloxy)-4-hydroxyquinoline-3-carboxylate 2 was obtained through the thermal condensation and cyclization of 6-benzyloxyaniline and ethyl ethoxymethylenemalonate, and subsequently transformed into its 4-chloro derivative 3 by treatment with POCl 3 (Scheme 1). 28 Finally, nucleophilic aromatic substitution with thiols or sodium thiolates provided the 4-thioalkyl derivatives 4–8 .…”

New QSAR Methods Applied to Structure−Activity Mapping and Combinatorial Chemistry

“…A data set was compiled from the literature. ,− It consisted of 321 compounds of diverse structure: benzodiazepines, arylpyrazolo-quinolines, β-carbolines, imidazo-pyridazines, and cyclopyrrolones. These were broken up into two sets: 21 compounds would serve as the test set, whilst the other 300 compounds would form the basis of training and validation sets.…”

“…In its simplest form the biological response is assumed to be a function of a number of molecular parameters which correlate with molecular size, lipid solubility, or electronic properties, e.g. pI 50 ) f(physicochemical parameters) QSAR has advantages of speed and simplicity, and it can, in some cases, account for some transport and metabolic processes which occur once the compound is administered. Hence, the method is often applicable to the analysis of in ViVo data.…”