PASS-predicted design, synthesis and biological evaluation of cyclic nitrones as nootropics Alka Marwaha, a R. K. Goel b, * and Mohinder P. Mahajan a, * a Department of Applied Chemistry, Guru Nanak Dev University, Amritsar 143005, Punjab, India b Department of Pharmaceutical Sciences and Drug Research, Punjabi University, Patiala, India Received 13 December 2006; revised 25 June 2007; accepted 27 June 2007 Available online 30 June 2007 Abstract—Out of 400 virtually designed imidazoline N-oxides, five cyclic nitrones were selected on the basis of PASS prediction as potent nootropics and were evaluated for their biological activities in albino mice. The selected N-alkyl and aryl-substituted nitrones were found to be excellent nootropics. A series of lead compounds acting as cognition enhancers have been provided, which can be further exploited in search of such New Chemical Entities (NCEs). Ó 2007 Elsevier Ltd. All rights reserved. One of the major challenges of the third millennium will be to restore normal brain functions in individuals suffer- ing from neurodegenerative diseases like Alzheimer’s dis- ease, Parkinson’s disease or from cognitive dysfunction, one of the main symptoms accompanying ageing, stroke, acute as well as chronic cerebrovascular diseases, inflam- mation, traumatic brain injury, intoxication and oth- ers. 1–4 Nootropics, also known as smart drugs or cognition activators, are the drugs that enhance mental functions especially under conditions of disturbed neural metabolism resulting from the lack of oxygen, electro- shock or age-related induced changes and facilitate infor- mation flow between cerebral hemispheres. This category of drugs is becoming especially critical on account of the rapidly growing segment of the victimized population. Antioxidants are gaining a paramount significance as a panacea for a large number of life-style diseases like age- ing, cancer, diabetes, cardiovascular and other degener- ative diseases, etc. Nitrones, by acting as excellent spin traps, have been known to oppose the oxidative damage and the associated challenges. 5 However, the mechanism with which nitrones operate as antioxidants does not lie solely in their spin-trapping tendency. Other mecha- nisms of action, well documented in the literature, involve inhibition of Nitric Oxide Synthase (iNOS) expression, as well as cytokine production, modulation of calcium homeostasis, glutamate regulation and apop- tosis. 5a The piracetam group of antiamnesic compounds works by several mechanisms to revitalise neural func- tion. By supplying glutamic acid analogues to the Kreb’s cycle they enhance glucose utilization in aerobic respira- tion, the major means by which animal cells extract chemical energy from sugars via ATP formation. This, in turn, raises phospholipid cAMP levels, thereby enhancing the function of dopamine and acetylcholine neurons. N O O NH 2 Piracetam - the original smart drug 2-Oxo-1-pyrrolidine Piracetam like nootropics revert amnesia induced by scopolamine and other amnesic drugs, electroconvulsant shocks and hypoxia by an unknown mechanism. They also function as antioxidants (structure comparable to vitamin C) and retard lipofuscin formation. But none of the mechanisms has, so far, gathered general consen- sus. Thus, years after the identification of piracetam, a unifying hypothesis on the mechanism of action is till lacking and this class of cognition enhancers, despite 0960-894X/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved. doi:10.1016/j.bmcl.2007.06.071 Keywords: Nootropics; ANOVA; Imidazoline N-oxides; Lipinski’s rule of five; PASS. * Corresponding authors. Tel.: +91 1832258802 09 (M.P.M.); e-mail: mahajanmohinderp@yahoo.co.in Bioorganic & Medicinal Chemistry Letters 17 (2007) 5251–5255