Synthesis of E- and Z-Pyrazolylacrylonitriles and their Evaluation as Novel Antioxidants Virinder S. Parmar, a, * Ajay Kumar, a Ashok K. Prasad, a Sanjay K. Singh, a Naresh Kumar, a Shubhasish Mukherjee, a Hanumantharao G. Raj, b Sanjay Goel, b William Errington c and Mohindar S. Puar d a Department of Chemistry, University of Delhi, Delhi-110 007, India b Department of Biochemistry, VP Chest Institute, University of Delhi, Delhi-110 007, India c Department of Chemistry, University of Warwick, Coventry CV4 7AL, England d Structural Chemistry Division, Schering Plough Research Institute, Kenilworth, NJ 07033-0539, USA Received 16 November 1998; accepted 13 February 1999 Abstract—A facile synthesis of (Z)- and (E)-2-(5-arylpyrazol-3-yl)-3-(pyrrol-2-yl)acrylonitriles and (Z)-2-(1,3-diarylpyrazol-5-yl)-3- (pyrrol-2-yl)acrylonitriles, and isomerisation of (Z)-2-(5-arylpyrazolyl)acrylonitriles to (E)-2-(5-arylpyrazolyl)acrylonitriles under basic conditions have been reported. (Z)-2-(1,3-Diarylpyrazolyl)acrylonitriles did not undergo isomerisation under the similar conditions. New compounds were identified on the basis of their spectral data ( 1 H-, 13 C-, 1 H- 1 H COSY, NOESY, NOE, HMQC NMR, IR, UV and EI mass). The structures of one acrylonitrile and five of their precursor 6-arylpyran-2-ones and cyano- methylpyrazoles were confirmed by X-ray crystallographic studies. Eects of pyrazolylacrylonitriles and their precursors on rat liver-microsomal lipid peroxidation were evaluated in vitro with a view to establish structure–activity relationship and to identify a lead compound. # 1999 Elsevier Science Ltd. All rights reserved. Introduction Pyrazoles and their derivatives are widely used as medi- cines, e.g. as antipyretic, 1,2 antiinflammatory, 3 gastric secretion stimulatory, 4 antidepressant, 5 against rheu- matoid arthritis, 6,7 antihypercholesterolemic agents, 8 antibacterial agents, 9 anticonvulsant agents, 10 anti- filarial agents, 11 etc. Along with the medicinal applica- tions, this class of compounds are also useful as agrochemicals, e.g. as herbicides, 12,13 fungicides, 14 pes- ticides 15 and insecticides, 15 and as dyestus, 16–18 in sunscreen materials 19 and as analytical reagents. 20 Very few pyrazole derivatives are naturally occurring, may be due to the diculty of living organisms to construct the NN bond. Owing to the widespread applications, synthesis and biological activity evaluation of pyrazoles and their derivatives have been a subject of intensive investigations as revealed by enormous literature covering the subject. Considerable progress has been made in recent years in relating ageing to oxidation in biological cells. The reactive oxygen species (ROS), cause of oxidation in biological cells, are basically involved in detoxification of invading organisms and chemicals, but stray ROS also initiate lipid peroxidation in healthy cells leading to diverse pathologies such as Alzheimer’s disease, athero- sclerosis, diabetes, Parkinson’s disease, etc. 21 Thus, reduction of the rate of these life-limiting metabolic processes by use of chemicals 22–24 has been a subject of current research. In recent years, we have reported the synthesis of several new pyrazoles, 25 pyrazolylcoumar- ins 26 and isoxazoles, 27 and studied their biological activities. 28 In continuation, we wish to report herein the synthesis of Z- and E-pyrazolylacrylonitriles and their eects on NADPH-catalysed liver-microsomal lipid peroxidation. Results and Discussion (Z)-2-(5-Arylpyrazol-3-yl)-3-(pyrrol-2-yl)acrylonitriles 4a–4h were prepared by coupling of pyrrole-2-carbox- aldehyde with the corresponding 5-aryl-3-cyano- methylpyrazoles 3a–3h 27,29 in quantitative yields according to the procedure outlined in Scheme 1 and described in detail in the Experimental. Arylpyrazoles 3a–3h, in turn were prepared in four steps starting with the condensation of ethyl cyanoacetate with carbon disulfide in sodium ethoxide, methylation of 0968-0896/99/$ - see front matter # 1999 Elsevier Science Ltd. All rights reserved. PII: S0968-0896(99)00056-5 Bioorganic & Medicinal Chemistry 7 (1999) 1425–1436 Key words: Arylpyrazoles; pyrazolylacrylonitriles; isomerisation; antioxidants; lipid peroxidation. * Corresponding author. Tel.: +91-11-725-6555/7206; fax: +91-11- 725 7206; e-mail: vparmar.duchem@axcess.net.in