Synthesis, Physico-Chemical Properties and DFT Calculations of New 2-(4- Arylpiperazine-1-yl)-1-(3-ethylbenzofuran-2-yl)ethanols As Potential Antihypertensive Agents

Zuzana      Mandelova; Radka      Opatrilova; Ivan      Raich; Jaroslav      Havlicek; Sandra      Kacerova; Tomas      Pekarek; Marcela      Tkadlecova; Petra      Staskova; Jiri      Dohnal; Jozef      Csollei; Josef      Jampilek

doi:10.2174/138527211794785154

Abstract

Six new arylpiperazinylbenzofurane derivatives as potential hybrid antihypertensive agents were designed and synthesised. The discussed compounds were prepared as free bases and subsequently they were transformed to hydrochloride salts. The position of protonation of nitrogen atoms in the piperazine ring in hydrochloride salts was determined by means of IR spectrometry and 13C CP/MAS and 15N CP/MAS NMR spectroscopy. Using these solid state analytical methods it was found that both nitrogen atoms were protonated. These results were supported by elemental analysis and also by ab initio/DFT calculations of partial charges and proton affinities. Physico- chemical properties of free bases and salts are discussed; especially partition and distributive coefficients log P and log D7.4, dissociation constants pKa and molecular surfaces and volumes. The experimental results were also subsequently correlated with ab initio/DFT calculations.

Keywords: Heteroarylethanolamines, Piperazine, CP/MAS NMR spectroscopy, IR spectrometry, Ab initio/DFT calculations, Physicochemical properties, hypertension, cardiovascular mortality, renal diseases, hypertrophy, β-blockers, Arylpiperazine substitution, chromatography, UV irradiation, titration