Bioisosteric synthesis of nitrogen containing derivatives of salicyl alcohol, their in vivo pharmacological studies with
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Med Chem Res (2013) 22:4677–4684 DOI 10.1007/s00044-013-0473-z
ORIGINAL RESEARCH
Bioisosteric synthesis of nitrogen containing derivatives of salicyl alcohol, their in vivo pharmacological studies with molecular modeling Nasir Ullah • Nazar Ul Islam • Gowhar Ali • Fazal Subhan Faridoon • Ikhtiar Khan
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Received: 13 August 2012 / Accepted: 6 January 2013 / Published online: 18 January 2013 Ó Springer Science+Business Media New York 2013
Abstract Starting with salicylaldehyde, compounds (I) [1-(2-hydroxybenzyl)piperidinium chloride] and (II) [4-carbamoyl-1-(2-hydroxybenzyl)piperidinium chloride] were prepared via multi step synthesis. The synthesized compounds were evaluated in vivo for their anti-inflammatory, analgesic, and anti-pyretic activities. Both compounds showed significant pharmacological profile when compared with reference standard, aspirin. In an attempt to understand the ligand–protein interaction in terms of the binding affinity, the synthetic molecule II was subjected to docking analysis using AutoDock which showed better binding modes with the active sites of COX’s enzymes. Keywords 1-(2-Hydroxybenzyl)piperidinium chloride 4-Carbamoyl-1-(2-hydroxybenzyl)piperidinium chloride Anti-inflammatory Anti-pyretic Analgesic Molecular docking
Introduction Pharmacological activities of drugs depend on their reception in the living system. In majority of cases, drugs
N. Ullah N. Ul Islam (&) Faridoon I. Khan Institute of Chemical Sciences, University of Peshawar, Peshawar 25120, Pakistan e-mail: [email protected] G. Ali F. Subhan Department of Pharmacy, University of Peshawar, Peshawar 25120, Pakistan N. Ul Islam Sarhad University of Sciences and Information Technology, Peshawar, Pakistan
work through complex mechanistic pathways which are controlled by many factors. It is mainly the chemical structure of a drug which determines its ultimate pharmacological responses. Some pharmacological activities are clinically desirable to treat a particular disease while others may be undesirable and may cause toxicity; so structural changes are required to minimize toxic effects and maximize health benefits. Salicin (Fig. 1), first reported by Machagan was used in the treatment of acute rheumatism and was obtained from willow bark (Salix alba) (Machagan, 1876). Salicin is a glycoside of saligenin (2-hydroxy methyl phenol; salicyl alcohol; Fig. 2), and is chemically related to aspirin and possesses almost comparable pharmacological activities. Salicin on hydrolysis results in liberation of saligenin. Phenolic hydroxyl group of saligenin is making a b-glucosidic bond with D-glucopyranose in salicin structure. We were interested in the replacement of methylene hydroxyl group with nitrogen to see desirable pharmacological activities. In general, it has been argued that exchanging one bioisostere for another enhances the biological and/or physical properties of a compound, without making significant changes in a chemical structure (Joseph et al., 1999). Recently, it has been reported that salicin acts
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