Synthesis, antimicrobial activity and conformational analysis of novel substituted pyridines: BF 3 -promoted reaction of hydrazine with 2-alkoxy pyridines Fatma E. Goda, a, * Alaa A.-M. Abdel-Aziz b and Omer A. Attef c a Department of Pharmaceutical Organic Chemistry, Faculty of Pharmacy, University of Mansoura, Mansoura 35516, Egypt b Department of Medicinal Chemistry, Faculty of Pharmacy, University of Mansoura, Mansoura 35516, Egypt c Department of Pharmaceutical Chemistry, Faculty of Pharmacy and Health Sciences, Ajman University of Science & Technology, Ajman, United Arab Emirates Received 4 December 2003; revised 22 January 2004; accepted 27 January 2004 Abstract—Some new 2-alkoxy-3-cyano-4,6-diarylpyridines 3,4 were synthesized by condensation of different a,b-unsaturated ketones 1 with malononitrile 2, followed by cyclization in sodium alkoxide/alcohol system. Lewis acid-catalyzed reaction of 4 with hydrazine afforded the corresponding 1H-pyrazolo[3,4-b]pyridines 5. The potency of the results as antimicrobial agents has been evaluated. The structure of the newly prepared compounds was assessed by microanalysis, IR and NMR spectra. Molecular mechanics (MM2) and semiemperical (AM1) molecular orbital calculations have been performed for the most biologically active compounds 5b and c to get insight into their molecular structures and to learn more about their stable molecular conformations. # 2004 Elsevier Ltd. All rights reserved. 1. Introduction The rising prevalence of multi-drug resistant Gram- positive and Gram-negative bacteria continues to provide impetus for the search and discovery of novel anti- microbial agents active against these pathogens. During the last two decades, a large number of substituted pyr- idines have been claimed to have several biological activities. 1 9 The antifungal and antibacterial properties of these compounds have opened up the possibility of their potential use as a novel class of totally synthetic antimicrobial agents active against pathogenic bacteria including Pesudomonas aeruginosa IFO 3448, Escher- echia coli IFO 3301, Staphylococcus aureus IFO 3060, Bacillus subtilis IFO 3007 and Candida albicans IFO 0583. 3 9 Moreover, 1H-pyrazolo[3,4-b]pyridines com- prise a very interesting class of compounds because of their significant and versatile biological and pharmaco- logical activities, such as antimicrobial, antimalarial, antiviral and antiproliferative. 9 16 2. Results and discussion 2.1. Chemistry In the view of those reports, new compounds containing 2-alkoxy pyridine moieties and their fused 1H-pyr- azolo[3,4-b]pyridines, have been designed to be tested as antimicrobial agents. It was reported that the reaction of chalcones with malononitrile and ethyl cyanoacetate in the presence of ammonium acetate and absolute eth- anol afforded cyanopyridines in low yield. 17,18 Simila- rily, the preparation of 2-alkoxy cyanopyridines in good yields was reported via Michael addition of mal- ononitrile to the /,b-unsaturated ketones. 19,20 In the present work /,b-unsaturated ketones 1 were con- densed with malononitrile in either sodium methoxide/ methanol or sodium ethoxide/ethanol to yield the corresponding cyanopyridines 3,4 in a good yield. It was observed that the increase in the carbon number of alkoxyl group caused much prolongation time of the reaction and relatively low yield (Scheme 1). The reac- tion proceeds through Michael addition of the /, b- unsaturated ketones to the malononitrile to afford adduct 2 which undergoes a nucleophilic attack by alk- oxide anion followed by cyclization. Subsequent dehy- dration of the cyclized product leads to the 2-alkoxy cyanopyridines 3 or 4. The structure was assigned on 0968-0896/$ - see front matter # 2004 Elsevier Ltd. All rights reserved. doi:10.1016/j.bmc.2004.01.040 Bioorganic & Medicinal Chemistry 12 (2004) 1845–1852 Keywords: Pyridine; 1H-pyrazolo[3,4-b]pyridines; Antimicrobial; Conformational analysis; Molecular mechanics; Semiemperical mole- cular orbital. * Corresponding author. Tel.:+20-50-2249155; fax: +20-50-2247496; e-mail: fatma_goda@yahoo.com