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Synthesis, characterization, in vitro hydrolysis and pharmacodynamic profiles of potential novel mutual prodrugs of N-(2,3-xylyl anthranilic acid)

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Abstract

In present research work, we report the synthesis, in vitro hydrolysis study and pharmacological evaluation of new mutual prodrugs of mefenamic acid (MA) and 1,2 dihydro-1,5-dimethyl-4-(1-methylethyl)-2-phenylpyrazol-3-one with the aim of improving the therapeutic potency and retard the adverse effects of gastrointestinal origin. The structure of the synthesized mutual ester prodrugs (MP1 and MP2) were confirmed by IR, 1H NMR, 13C NMR, mass spectroscopy and their formation was confirmed by TLC. The purity of the synthesized compounds was established by elemental analysis. The title compounds were tested for analgesic activity by acetic acid-induced writhing method; anti-inflammatory activity was tested by carrageenan-induced rat paw edema method and ulcerogenicity. The study of the analgesic activity revealed that both prodrugs (MP1 and MP2) have shown significant reduction (81.67, 63.90 %) in writhing response produced by acetic acid as compared to parent drug MA (61.10 %). Both mutual prodrugs showed better maximum anti-inflammatory effects (71.43, 85.71 %) and for longer time as compared to parent drug MA (53.14 %). The synthesized prodrugs were also found to be very less irritating to gastric mucosal membrane than parent drugs. The kinetics of ester hydrolysis was studied in simulated gastric fluid (SGF) at pH 1.2 and simulated intestinal fluid (SIF) at pH 7.4. The release of free MA from prodrugs showed negligible hydrolysis in SGF as compared to SIF. This indicated that prodrugs were sufficiently stable at pH 1.2 and do not break in the stomach, but release MA in SIF.

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Acknowledgments

The authors express their thanks to Vani Pharma Labs Limited, Hyderabad (Andhra Pradesh), India, for providing gift sample of propyphenazone. The authors are grateful to Head of Department, Department of Pharmaceutical Sciences, Maharshi Dayanand University, Rohtak (Haryana), India, for providing the necessary facilities to carry out this work.

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Authors and Affiliations

  1. Hindu College of Pharmacy, Sonepat, 131001, India

    Sucheta Ohlan

  2. Department of Pharmaceutical Sciences, M. D. University, Rohtak, 124001, India

    Sanju Nanda

  3. Delhi Institute of Pharmaceutical Sciences & Research (DIPSAR), New Delhi, 110017, India

    Dharam Pal Pathak

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  1. Sucheta Ohlan
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  2. Sanju Nanda
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  3. Dharam Pal Pathak
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Correspondence to Sucheta Ohlan.

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Ohlan, S., Nanda, S. & Pathak, D.P. Synthesis, characterization, in vitro hydrolysis and pharmacodynamic profiles of potential novel mutual prodrugs of N-(2,3-xylyl anthranilic acid). Med Chem Res 22, 5120–5128 (2013). https://doi.org/10.1007/s00044-013-0516-5

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