Original article Applications of 2-arylhydrazononitriles in synthesis: Preparation of new indole containing 1,2,3-triazole, pyrazole and pyrazolo[1,5-a]pyrimidine derivatives and evaluation of their antimicrobial activities Haider Behbehani a, * , Hamada Mohamed Ibrahim a, b , Saad Makhseed a , Huda Mahmoud c a Chemistry Department, Faculty of Science, Kuwait University, P.O. Box 5969, Safat 13060, Kuwait b Chemistry Department, Faculty of Science, Fayoum University, Fayoum, Egypt c Biology Department, Faculty of Science, Kuwait University, P.O. Box 5969, Safat 13060, Kuwait article info Article history: Received 28 October 2010 Received in revised form 13 February 2011 Accepted 15 February 2011 Available online 23 February 2011 Keywords: Cyanoacetamides 5-Amino-1,2,3-triazole Enaminonitrile Pyridine-6-carbonitrile Antimicrobial activity abstract In this effort, 2-arylhdrazononitriles were used as key synthons for the preparation of wide variety of new, uniquely substituted heterocyclic substances. In addition, the results of biological evaluations demonstrate that members of the group prepared have promising antimicrobial activities against Gram negative bacteria, Gram positive bacteria and Yeast. In the synthetic sequences, 3-(1-methyl-1H-indol-3- yl)-3-oxo-2-(phenylhydrazono)propanenitrile 2a and its 2-methyl derivative 2b were found to react with hydroxylamine hydrochloride to yield the corresponding indolyl-5-amino-2-phenyl-1,2,3-triazoles 4a,b. These amines react with cyanoacetic acid in presence of acetic anhydride either thermally or under microwave irradiation conditions to yield the corresponding cyanoacetamides 5a,b, which condensed readily with dimethylformamide dimethylacetal to yield the enaminonitriles 6a,b. Whereas heating of 6a,b with hydrazine hydrate affords compound 8, compound 12 is produced when these reactants are subjected to microwave irradiation. We observed that the aminopyrazole 9 reacts with enaminal 13 to yield 14 and that its reactions with enaminones 15 afford 17 . Finally, compound 5 reacts with cinna- maldehyde to yield the corresponding Schiff’s base 18 that does not undergo cyclization to form the pyridine derivative 19. The activities of all new substances synthesized in this investigation were eval- uated against a panel of microbial organisms. The results show that 4a, 4b, 5b and 9b display strong antimicrobial activities against all of the tested organisms. Ó 2011 Elsevier Masson SAS. All rights reserved. 1. Introduction Owing to their interesting biological activities and medicinal properties [1e 7], indole derivatives have been targets of investi- gations by several research groups [8e11]. Also, the 1,2,3-triazole ring system has been the focus of numerous studies owing to its importance in industrially interesting materials, such as dyes, anticorrosive agents, photo stabilizers, photographic materials, and agrochemicals [12]. Although the 1,2,3-triazole structural moiety does not occur in nature, it may display biological activities and there are numerous examples in the literature including anti-HIV [13], anti-Gram positive bacterial [14,15], anti-allergic [16,17], anti- convulsant [18], b-lactamase inhibitory [19], selective b3 adrenergic receptor agonism [20], anti-tuberculosis [21] activities. The antici- pated biological properties of interesting aroyltriazolylamines that incorporate the indole moiety has encouraged us to explore their synthesis and elucidate their biological activities. Below, we describe the results of an investigation aimed at the preparation of these substances and an evaluation of their biological properties. 2. Result and discussion 2.1. Synthetic chemistry We recently described an efficient synthesis of the cyanoacetyl- indole derivative 1a that can be easily converted to the corre- sponding hydrazone 2a [11], a potentially important synthon in synthetic routes targeted at new aroyl-heteroaromatic substances. In an extension of our previous effort leading to the synthesis of 2- substituted-1,2,3-triazole-5-amines [11], we have utilized hydra- zones 2a,b as precursors of new indolyl heteroaromatic substances. The investigation aimed at this goal began with the reactions of 2a,b with hydroxylamine hydrochloride in the presence of sodium acetate, promoted by heating in DMF solutions for 3 h or using microwave irradiation for 60 s. Under these conditions, * Corresponding author. Tel.: þ965 99063062; fax: þ965 24843891. E-mail address: hbehbehani@hotmail.com (H. Behbehani). Contents lists available at ScienceDirect European Journal of Medicinal Chemistry journal homepage: http://www.elsevier.com/locate/ejmech 0223-5234/$ e see front matter Ó 2011 Elsevier Masson SAS. All rights reserved. doi:10.1016/j.ejmech.2011.02.040 European Journal of Medicinal Chemistry 46 (2011) 1813e1820