Lipophilicity of Aminopyridazinone Regioisomers M ASSUDA. S. ANWAIR , § LAÄ SZLOÄ KAÄ ROLYHAÄ ZY , § D IAÄ NA S ZABOÄ , § B ALAÄ ZS B ALOGH , § I STVAÄ N KO¨ VESDI , † VERONIKA H ARMAT , ‡ JUDIT KRENYAÄ CZ , ‡ AÄ KOS G ELLEÄ RT , ‡ KRISZTINA TAKAÄ CS -N OVAÄ K ,* ,# AND P EÄ TER M AÄ TYUS * ,§ Departments of Organic Chemistry and Pharmaceutical Chemistry, Semmelweis University, Ho _gyes E.u.7-9, 1092 Budapest, Hungary; Vichem Chemie Ltd., Hermann O. u.15, 1022 Budapest, Hungary; and Department of Theoretical Chemistry, Eo¨tvo¨s Lora´nd University, Pa´zma´ny Pe´ter se´ta´ny 1, 1117 Budapest, Hungary 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(2 H )-pyridazinone regioisomers were synthesized by nucleophilic substitution of one of the chloro atoms of 4,5-dichloro-2-methyl-3(2 H )- 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 So¨ rensen buffer (pH 7.4) solvent system. A consequent difference was found in the lipophilicity of regioisomers. For each isomer pair, the log P value ofthe 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 prioriKOWWIN gave poor agreement, butwith the programs KOWWIN with EVA (experimental value adjusted) and 3DNET, the results were generally in agreement with experiment. KEYWORDS:Aminopyridazinone regioisomers; nucleophilic substitution; octanol/water partitioning; log P ; log Pcalculators; X-ray INTRODUCTION 3(2H)-Pyridazinones substituted with an amino group at the 5-position represent an important and thoroughly investigated classof pesticides. Somerepresentatives of this classof compounds have been marketed and used in practice ( 1). We have also discovered several aminopyridazinones with remarkable biological activities; for example, antiarrhythmic (2), nootropic (memory-improving) (3), and,more recently, anti- fungal(4) effectshave beenobserved. The most active compounds of the antifungal series of pyridazinones were found to exhibitantagonistic effects againsta broad spectrum of pathogenic fungii including Saccharomyces cereVisiae. Most probably, the antifungal activity of these compounds is related to the inhibitory action against â1,3-glucan synthase and chitin synthase enzymes thatcatalyze the synthesis of the major polymers of the fungal cell wall. Further in vitro and in vivo studies are now in progress to exploit these valuable properties; the agricultural and sanitation fields have been primarily considered for application. Interestingly, in almost all of the above series of pyridazi- nones,significant differences in the biological activitiesof regioisomeric 4- and 5-amino compounds have been detected For thesedifferentbiologicalactivities, the difference in hydrophobicity of the regioisomers may be expected to be at least partially responsible. Therefore, we thought that a com- parison of the logarithm of the octanol/water partition coef- ficients (i.e., log P values) of the regioisomers might provide useful information. Indeed, our preliminary study on two pair of regioisomers (2c,g and 3c,g, Scheme 1) revealed that log values of the 4-amino isomers were significantly higher (5), supporting the idea that there might be some correlation bet the antifungal activity and log P of regioisomers. The literature showed that, apart from our preliminary wor and the excellent well-known study of Testa etal. on the influence of stereochemical factors on the log P of diastereo- mers,no relevant study has been done on the lipophilicity of regioisomers (6). Testa et al. found that some pairs of diaster eomers showed the same lipophilicity, whereas others display differences of up to 1 log unit. For rigid compounds with one polar group, differences in lipophilicity were related to differ- ences in solvent accessible surface area. For flexible compou * Corresponding authors [(P.M.) fax/telephone +36-1-217-0851, e-mail matypet@szerves.sote.hu; (K.T.-N.) fax +36-1-2170890, telephone +36- 1-2155241, e-mail novkri@hogyes.sote.hu. † Vichem Chemie Ltd. ‡ Eo¨tvo¨s Lora´nd University. § Department of Organic Chemistry, Semmelweis University. # Department of Pharmaceutical Chemistry, Semmelweis University. 5262 J. Agric. Food Chem. 2003, 51, 5262 − 5270 10.1021/jf0343938 CCC: $25.00 © 2003 American Chemical Society Published on Web 07/25/2003