title: Lipophilicity of aminopyridazinone regioisomers.
abstract: Ten pairs of pyridazinone regioisomers were prepared, and their lipophilicity was described by the logarithm of the octanol/water partition coefficient (log P) determined experimentally and calculated with prediction methods. The 4- and 5-(substituted amino)-3(2H)-pyridazinone regioisomers were synthesized by nucleophilic substitution of one of the chloro atoms of 4,5-dichloro-2-methyl-3(2H)-pyridazinone or its 6-nitro derivative. Structures of new compounds were proven by spectroscopic methods. The experimental log P values were obtained by a shake flask method in octanol and a Sörensen buffer (pH 7.4) solvent system. A consequent difference was found in the lipophilicity of regioisomers. For each isomer pair, the log P value of the 4-isomer was significantly (average by 0.75 log unit) higher than that of the 5-isomer. Some quantum chemical calculations as well as X-ray analysis of two pairs of regioisomers were also carried out to gain insight into the structural differences of regioisomers. The log P values were calculated by the fragmental approach KOWWIN and a QSPR analysis (3DNET). The a priori KOWWIN gave poor agreement, but with the programs KOWWIN with EVA (experimental value adjusted) and 3DNET, the results were generally in agreement with experiment.
authors.affiliation: Department of Organic Chemistry, Semmelweis University, Hogyes E. u. 7-9, 1092 Budapest, Hungary.
authors.forename: Massud A S
authors.initials: MA
authors.lastname: Anwair
authors.forename: László
authors.initials: L
authors.lastname: Károlyházy
authors.forename: Diána
authors.initials: D
authors.lastname: Szabó
authors.forename: Balázs
authors.initials: B
authors.lastname: Balogh
authors.forename: István
authors.initials: I
authors.lastname: Kövesdi
authors.forename: Veronika
authors.initials: V
authors.lastname: Harmat
authors.forename: Judit
authors.initials: J
authors.lastname: Krenyácz
authors.forename: Akos
authors.initials: A
authors.lastname: Gellért
authors.forename: Krisztina
authors.initials: K
authors.lastname: Takács-Novák
authors.forename: Péter
authors.initials: P
authors.lastname: Mátyus
mesh_terms: D055598:Chemical Phenomena; D002627:Chemistry, Physical; D003460:Crystallization; D018360:Crystallography, X-Ray; D007536:Isomerism; D008055:Lipids / Q000737:chemistry*; D008958:Models, Molecular; D015394:Molecular Structure; D000442:Octanols; D011724:Pyridazines / Q000737:chemistry*; D014867:Water
chemical_list: D008055:Lipids; D000442:Octanols; D011724:Pyridazines; D014867:Water