Synthesis and Biological Evaluation of Some New Rhodanine Analogues as Aldose Reductase Inhibitors (ARIs)
Diabetes mellitus is a metabolic disorder characterized by hyperglycemia resulting long-term secondary complication. Aldose reductase, the rate-limiting enzyme of the polyol pathway, plays a key role in the treatment of diabetic complications. Appropriately, inhibition of this enzyme is emerging as a major therapeutic strategy for the pathogenesis of secondary complication. In this study, we describe a series of 5 aryl benzylidene -thiazolidine, 4-dione derivatives, F3 synthesized as aldose reductase inhibitors. Besides inhibiting efficiently the target enzyme, F4 and F5 showed additional AR inhibitory as well as hypoglycaemic activity (146.15 and 175.20 mg/dl ) thus emerging as novel dual acting compounds. The bezylidene derivative F3, the most promising of the whole series, showed a well-balanced, consisting of ALR2 inhibitory efficacy (83.00% at 10µg/mL), similarly, F3 have lower blood glucose level in the range of 131.11 mg/dl at 15 mg/kg body weight. This compound show robust in vitro and in vivo efficacy, and could be considered as promising dual target antidiabetic drug candidates.
Keywords: Diabetes mellitus, hyperglycemia, Aldose reductase inhibitors
2. Yang W., Lu J., Weng J., Jia W., Ji L; Prevalence of diabetes among men and women in China. N Engl J Med 2010, 362, 1090-1101.
3. Xu Y., Wang L., He J., Bi Y., Li M.; Prevalence and control of diabetes in Chinese adults. JAMA 2013, 310, 948-959.
4. Brownlee M; Biochemistry and molecular cell biology of diabetic complications. Nature, 2001, 414, 813-820.
5. Maccari R., Vitale R.M., Ottan R., Rocchiccioli M., Marrazzo A.; Structure–activity relationships and molecular modelling of new 5-arylidene- 4-thiazolidinone derivatives as aldose reductase inhibitors and potential anti-inflammatory agents. European Journal of Medicinal Chemistry, 2014, 1-14.
6. Patel A.B, Kumari P.; Scope of Selective Heterocycles from Organic and Pharmaceutical Perspective http://dx.doi.org/10.5772/62835
7. Ernst R, Roland N.I., Gordon A.A. Rhodanine. Org. Synth. 1947, 27, 73.
8. Nencki, M. Ueber die einwirkung der monochloressigsaure auf sulfocyansaure und ihre salze. J. Prakt. Chem. 1877, 16, 1–17.
9. Zidar N., Tomasic. T., Sink V. R.,, Rupnik, A. Kovac, Turk S., Patin D., Blanot D., Martel C.C., A. Dessen, Premru M. M, Zega A, Gobec S., Masic L.P., Kikelj, D. J. Med. Chem., 2010, 53, 6584–6594.
10. N. Zidar, T. Tomasic, R. Sˇink, A. Kovac, D. Patin, D. Blanot, C. Contreras- Martel, A. Dessen, M. M. Premru, A. Zega, S. Gobec, L. P. Masic, D. Kikelj.; Eur. J. Med. Chem., 2011, 46, 5512–5523.
11. Tomasic. T., Zidar N., Sink V. R.,, Rupnik, A. Kovac, Turk S., Patin D., Blanot D., Martel C.C., A. Dessen, Premru M. M, Zega A, Gobec S., Masic L.P., Kikelj,D., J. Med. Chem., 2011, 54, 4600–4610.
12. Tomasic. T., Zidar N., Sink V. R.,, Rupnik, A. Kovac, Turk S., Patin D., Blanot D., Martel C.C., A. Dessen, Premru M. M, Zega A, Gobec S., Masic L.P., Kikelj,D., ACS Med. Chem. Lett., 2012, 3, 626–630.
13. Tomasic. T., Zidar N., Turk S., Simcic M., Blanot D., Muller- Premru M. Filipic, Grdadolnik S. G., Zega A., Anderluh M., Gobec S., Kikelj D., Masic L.P., ChemMedChem, 2010, 5, 286–295.
14. Tomasic T., Kovac A., Simcic M., Blanot D., Grdadolnik S. G, Gobec S., Kikelj D., Masic L. P.; Eur. J. Med. Chem., 2011, 46, 3964–3975.
15. T. Mendgen, C. Steuer and C. D. Klein, J. Med. Chem., 2012, 55, 743–753.
16. Constantino L., Rastelli G., Vianello P., Cignarella G., Barlocco D.; Diabetes complications and their potential prevention: aldose reductase inhibition and other approaches. Med Res Rev 1999, 19, 3-23.
This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License.
Authors who publish with this journal agree to the following terms:
- Authors retain copyright and grant the journal right of first publication with the work simultaneously licensed under a Creative Commons Attribution-NonCommercial 4.0 International (CC BY-NC 4.0). that allows others to share the work with an acknowledgment of the work's authorship and initial publication in this journal.
- Authors are able to enter into separate, additional contractual arrangements for the non-exclusive distribution of the journal's published version of the work (e.g., post it to an institutional repository or publish it in a book), with an acknowledgment of its initial publication in this journal.
- Authors are permitted and encouraged to post their work online (e.g., in institutional repositories or on their website) prior to and during the submission process, as it can lead to productive exchanges, as well as earlier and greater citation of published work (See The Effect of Open Access).