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Ulcerogenicity devoid novel non-steroidal anti-inflammatory agents (NSAIDS): syntheses, computational studies, and activity of 5-aryliden-2-imino-4-thiazolidinones

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Abstract

A series of new 5-aryliden-2-imino-4-thiazolidinones (5a–e and 6a–e) were synthesized via a three-step reaction and characterized by physicochemical and spectral data. The uniqueness of the derivatives lies in the fact that none of them had an acidic group, like conventional NSAIDS, but exhibited significant in vivo activity in acute inflammation models. In particular, 5-(3-chlorobenzyliden)-2-(pyridin-2-yl-imino)-4-thiazolidinone(5a) and 5-(3-chlorobenzyliden)-2-(5-methylisoxazol-3-yl-imino)-4-thiazolidinone (6a) showed remarkable paw oedema inhibition (67.76 and 74.47 % oedema inhibition, respectively, after 3 h) comparable to that of Ibuprofen (74.56 % oedema inhibition, after 3 h) at half of the dose of the standard drug. Also, compounds 5a (72.86 %) and 6a (80.20 %) were found to possess significant inhibition of albumin denaturation when screened for in vitro anti-inflammatory activity. In addition, these compounds were docked into the known active site of COX-2 protein using Glide XP and QPLD algorithms, and the binding-free energy was calculated using Prime MM/GBSA simulation methods. The combined use of molecular docking and MM/GBSA methods gave a good correlation between the predicted binding-free energy and experimentally determined biological activities. It was also evident from the docking results that 2-methylisoxazolylimino or 2-(pyridin-2-yl-imino substitution and 3-chloro moiety on 5-benzylidin nucleus of these 4-thiazolidinone derivatives can easily occupy the COX-2 binding pocket, considered as the critical interaction for COX-2 inhibition. Moreover, pharmacokinetic properties of all the synthesized compounds were predicted, with good results. Further, the synthesized derivatives showed neither acute toxicity nor symptoms of gastric ulceration, at extended doses, owing to the absence of an acidic group.

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Acknowledgments

This study was funded by the All India Council for Technical Education (AICTE), New Delhi, India, under the Research Promotion Scheme (RPS).

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Authors and Affiliations

  1. Division of Pharmaceutical Chemistry, Faculty of Pharmacy, Babu Banarasi Das Northern India Institute of Technology, BBD City, Faizabad Road, Chinhut, Lucknow, 226028, U.P., India

    Neha Singh, Avinash C. Tripathi, Aseem Tewari & Shailendra K. Saraf

  2. Schrodinger Inc, New York, USA

    Ravi Kumar

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  1. Neha Singh
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  2. Avinash C. Tripathi
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  3. Aseem Tewari
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Correspondence to Shailendra K. Saraf.

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Singh, N., Tripathi, A.C., Tewari, A. et al. Ulcerogenicity devoid novel non-steroidal anti-inflammatory agents (NSAIDS): syntheses, computational studies, and activity of 5-aryliden-2-imino-4-thiazolidinones. Med Chem Res 24, 1927–1941 (2015). https://doi.org/10.1007/s00044-014-1270-z

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  • DOI: https://doi.org/10.1007/s00044-014-1270-z

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