Lewis acid-promoted transformation of 2-alkoxypyridines into 2-aminopyridines and their antibacterial activity. Part 2: Remarkably facile C–N bond formation Alaa A.-M. Abdel-Aziz, a, * Hussein I. El-Subbagh b and Takehisa Kunieda c a Department of Medicinal Chemistry, Faculty of Pharmacy, University of Mansoura, Mansoura 35516, Egypt b Department of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, Riyadh 11451, Saudi Arabia c Faculty of Pharmaceutical Sciences, Sojo University, Kumamoto 860-0082, Japan Received 23 February 2005; revised 15 May 2005; accepted 18 May 2005 Abstract—2-Alkoxy-3-cyano-4,6-diarylpyridines 1a,b which were synthesized by condensation of a,b-unsaturated ketones with malononitrils were subjected to Lewis acid-catalyzed nucleophilic displacement reaction with various amines to afford the corre- sponding 2-aminopyridines 3–21. The potency of the results as antibacterial agents has been evaluated. The structure of the newly prepared compounds was assessed by microanalysis, IR, and NMR spectra. Molecular modeling and QSAR methods are used to study the antibacterial activity of the active compounds by means of the molecular mechanic method. Ó 2005 Elsevier Ltd. All rights reserved. 1. Introduction The rapid development of resistance in clinically impor- tant Gram-positive bacteria represents a serious public health threat. 1 Staphylococcus aureus is a common cause of many skin and mucous membrane infections. Many strains have developed resistance and antibiotic treat- ment options have become more limited. 2,3 Actually, no new classes of antibiotics have been intro- duced to the market in the 37 years between the introduc- tion of nalidixic acid in 1962 and linezolid in 2000. All the antibacterials introduced in this period were modifica- tions of existing molecules. Bacteria have exploited this window of opportunity by developing resistance to all commonly used antibiotics, making the need for new anti- biotics more pressing. 4 Therefore, the antifungal and anti- bacterial properties of substituted pyridines have opened up the possibility of their potential use as a novel class of totally synthetic antimicrobial agents. 5 2-Aminopyridines are promising substituted pyridines which have been shown to be biologically active molecules. 6,7 Additional- ly, because of their chelating abilities, 2-aminopyridines are commonly used as ligands in inorganic and organo- metallic chemistry. 8 If substituted with optically active groups, they could potentially serve as chiral auxiliaries or chiral ligands in asymmetric reactions. For these rea- sons, 2-aminopyridines are valuable synthetic targets. The synthesis of 2-aminopyridine derivatives has been extensively reviewed. 6–13 2-(Substituted amino)pyridines were previously mostly prepared: (i) by reaction of pri- mary or secondary aliphatic amines with 2-halopyridines or with imidol silyl ethers derived from the corresponding pyrid-2-ones, 14 (ii) by aminolysis of 2-alkoxypyridines, 15 and (iii) by using methodology previously described by Katritzky et al. 16 Of these methods, pathway (i) requires high temperatures and high pressure while pathway (ii) proceeds with alkoxypyridines containing activating groups in the pyridine ring under strong basic condition, high temperatures, and long reaction time. Method (iii) worked reasonably well with simple secondary amines while it was unable to isolate any of the desired 2-amino- pyridine products when anilines or primary amines were employed as nucleophiles. Hence, a versatile route for the synthesis of N-substituted 2-aminopyridines utilizing primary and secondary amines as nucleophiles under mild condition is highly desirable. In a previous paper, 5 we reported the synthesis of 4, 6-diaryl-3-cyano-2-alkoxypyridines and their reaction 0968-0896/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved. doi:10.1016/j.bmc.2005.05.027 Keywords: Lewis acid; 2-Alkoxypyridines; 2-Aminopyridines; Anti- bacterial activity; Molecular modeling. * Corresponding author. Tel.: +2 050 2351626; fax: +2 050 2247496; e-mail: alaa_moenes@yahoo.com Bioorganic & Medicinal Chemistry 13 (2005) 4929–4935