Bis(het)aryl-1,2,3-triazole quinuclidines as α7 nicotinic acetylcholine receptor ligands: Synthesis, structure affinity relationships, agonism activity, [F]-radiolabeling and PET study in rats.

In this paper we describe the design and synthesis of bis(Het)Aryl-1,2,3-triazole quinuclidine α7R ligands using an efficient three-step sequence including a Suzuki-Miyaura cross coupling reaction with commercially available and home-made boron derivatives. The exploration of SAR required the preparation of uncommon boron derivatives. Forty final drugs were tested for their ability to bind the target and nine of them exhibited Ki values below nanomolar concentrations.

Design of α7 nicotinic acetylcholine receptor ligands using the (het)Aryl-1,2,3-triazole core: Synthesis, in vitro evaluation and SAR studies.

We report here the synthesis of a large library of 1,2,3-triazole derivatives which were in vitro tested as α7 nAchR ligands. The SAR study revealed that several crucial factors are involved in the affinity of these compounds for α7 nAchR such as a (R) quinuclidine configuration and a mono C-3 quinuclidine substitution. The triazole ring was substituted by a phenyl ring bearing small OMe/CH2F groups or fluorine atom and by several heterocycles such as thiophenes, furanes, benzothiophenes or benzofuranes.

Design of α7 nicotinic acetylcholine receptor ligands in quinuclidine, tropane and quinazoline series. Chemistry, molecular modeling, radiochemistry, in vitro and in rats evaluations of a [(18)F] quinuclidine derivative.

In this report, we describe the synthesis of a novel library of α7 nAChR ligands based on the modulation of the quinuclidine, quinazoline and tropane moieties. Spirane derivatives were newly synthesized under stereo specific 1,3 dipolar cylcoadditions. Only amide derivatives bonded efficiently to the receptor with Ki measured between 14 and 133 nM.

A domino N-amidoacylation/aldol-type condensation approach to the synthesis of the topo-I inhibitor Rosettacin and derivatives.

The pot, atom, and step-economic synthesis of Rosettacin topo-I poison and its derivatives has been achieved using a novel domino N-amidoacylation/aldol-type condensation, followed by decarboxylation of the ester function. The key domino procedure simply involves mixing HOBt ester as new reagent with lactam and NaH together in THF or THF/ DMF. The reaction seems to be general and led to suitable N-heterocyclic products in moderate to good yields.

Intermolecular and intramolecular alpha-amidoalkylation reactions using bismuth triflate as the catalyst.

Bismuth(III) triflate was found to promote the formation of stable cyclic N-acyliminium species in remarkable catalytic amounts (1 mol %). The alpha-amidoalkylation process seems to be effective in intermolecular and intramolecular manners leading to alpha-substituted lactams and heterocyclic systems containing azacycles, respectively. By comparing our results with those obtained with the classical Lewis acids as catalysts, it was evidenced clearly that the use of bismuth(III) triflate had been efficient for nearly all alpha-acetoxy lactams we used, except for N-acyliminium precursors bearing a sulfur atom.