Sep-Oct 2007 Pyridazine and Phthalazine Derivatives with Potential Antimicrobial Activity 1149 Roxana M. Butnariu, 1 Maria D. Caprosu, 1 Vasilichia Bejan, 1 Margareta Ungureanu, 2 Antonia Poiata, 2 Cristina Tuchilus, 2 Margareta Florescu 3 and Ionel I. Mangalagiu 1 * 1 “Al. I. Cuza” University of Iasi, Organic and Biochemistry Department, Bd. Carol 11, 700506 Iasi, Romania. e-mail: ionelm@uaic.ro 2 University of Medicine and Pharmacy “Gr.T.Popa” Iasi, Str. Universitatii 16, 700115 Iasi, Romania. 3 Academy of Economical Sciences, Str. Piata Romana 6, Sector 1, 010374 Bucuresti, Romania. e-mail: icefaceus@yahoo.com Received May 9, 2006 N N R O CH 3 N N C H R O CH 3 Z-dipolarophiles Z Z Fifteen new pyridazine and phthalazine derivatives were prepared (in good to excellent yields) and tested in vitro as antimicrobial compounds. All the compounds have proved to have a remarkable activity against Gram positive germs, the results on Sarciria Luteea being spectacular. Correlation structure - biological activity have been done. Stereo- and region- chemistry involved in these reactions are discussed. J. Heterocyclic Chem., 44, 1149 (2007). INTRODUCTION The literature describes a large variety of pyridazine and phthalazine compounds (1) with different biological activities: anticancer [1,2], antituberculosis [3], antimicrobial [4-6], antihypertensive [7-9], platelent aggregation inhibitor [9,10], etc. A facile way to obtain diazine derivatives uses cycloimmonium ylides as reactive species [11-15]. The reaction pathway involves, in the most frequent cases, a Huisgen 3+2 dipolar cycloaddition of ylides to dipolarophiles (activated alkenes and alkynes). The problems of stereo- and regiochemistry involved in these types of cycloadditions are discussed. N N 1 N N 2 R O CH 3 I II X Considering the pyridazine – acetophenone skeleton (2) as the pharmacophoric group for the activity [4,9], in this work we aimed to obtain new diazine heterocycles with antimicrobial activity, having in mind three structural modifications: introduction of a pyrrolo (I) and/or a benzene (II) ring, and a substituient (R). In equal measure, we were interested in the chemistry of cycloaddition reactions. In order to synthetise the desired pyridazine and phthal- azine derivatives, first we obtained the corresponding cycloimmonium salt (3) which in alkaline medium (Et 3 N) generated the ylide (4) in situ. N-Phenylmaleimide (NPMI), as a symmetrical cyclic Z-alkene, reacts with ylides (4) giving the cycloadduct (5). The Huisgen 3+2 cycloaddition occurs with high stereospecificity and no formation of other isomers was observed. The reaction of ylides (4) with dimethyl acetyl- endicarboxylate (DMAD) leads to pyrrolopyridazine (8a) and dihydropyrrolophthalazines (8b,c). As to the mechanism, the formation of compounds (8b,c) could be explained by prototropic rearrangement of (7b,c) while N N CH 2 Br N N CH COC 6 H 4 Me-4 N N BrCH 2 COC 6 H 4 Me-4 C O Me N N CH COC 6 H 4 Me-4 1 6 9 7 12 N N CH 2 4.a Br N N CH COC 6 H 4 Me-4 N N C O Me N N CH COC 6 H 4 Me-4 3.a 9 1 8 4 3.b. R= H c. R= Me 4.b. R= H c. R= Me R R R R 11 14