Medicinal Chemistry Research

, Volume 22, Issue 1, pp 70–77 | Cite as

Evaluation of mefenamic acid mutual prodrugs

  • Kamal ShahEmail author
  • Sushant K. Shrivastava
  • Pradeep Mishra
Original Research


Mutual prodrugs consisting of mefenamic acid with menthol and thymol have been synthesized as a gastrosparing NSAIDs, devoid of ulcerogenic side effects. The structures of synthesized esters were confirmed by IR, 1H NMR, and mass spectroscopy. The kinetics of ester hydrolysis was studied in nonenzymatic buffer solutions, at pH 2 and 7.4 as well as in human plasma by HPLC. Its anti-inflammatory, analgesic, and ulcerogenic activities were evaluated. Then biochemical parameters (GWM and Hexosamine), oxidative parameters (LPO, GSH, CAT, and SOD), and protein estimation was also done. The results indicated that synthesized prodrugs are chemically stable, biolabile, and posses optimum lipophilicity. The synthesized prodrugs are characterized by better ulcer index than the parent drug.


Mutual prodrug Mefenamic acid Kinetics Ulcerogenic Oxidative stress parameters 



Authors thank M/S Zydus Cadila, Ahmedabad, Gujarat, India for providing mefenamic acid as gift sample and to Vice Chancellor, GLA University, Mathura UP, India for providing the research facilities to carry out this work in the Institute of Pharmaceutical Research.


  1. Abraham M, Rudolph MD (1981) Effects of aspirin and acetaminophen in pregnancy and in the newborn. Arch Inter Med 141(3):358–363. doi: 10.1001/archinte.1981.00340030090016 CrossRefGoogle Scholar
  2. Bandyopadhyay U, Das D, Banerjee RK (1999) Reactive oxygen species: oxidative damage and pathogenesis. Curr Sci 77:658–665Google Scholar
  3. Blumenkrantz N, Asboe-Hansen G (1976) An assay for total hexosamine and a differential assay for glucosamine and galactosamine. Clin Biochem 9(6):269–274. doi: 10.1016/S0009-9120(76)80075-6 PubMedCrossRefGoogle Scholar
  4. Bradford MM (1976) A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding. Ana Biochem 72:248–254. doi: 10.1016/0003-2697(76)90527-3 CrossRefGoogle Scholar
  5. Corne SJ, Morrissey SM, Woods RJ (1974) Proceedings: a method for the quantitative estimation of gastric barrier mucus. J Physiol 242:116–117Google Scholar
  6. Ellman GL (1959) Tissue sulfhydryl groups. Arch Biochem Biophy 82:70–77. doi: 10.1016/0003-9861(59)90090-6 CrossRefGoogle Scholar
  7. Gibson T (1988) Nonsteroidal anti-inflammatory drugs: another look. Br J Rheumatol 27:87–90. doi: 10.1093/rheumatology/27.2.87 PubMedCrossRefGoogle Scholar
  8. Hassan A, Martin E, Puig-Parellada P (1998) Role of antioxidants in gastric mucosal damage induced by indomethacin in rats. Methods Find Exp Clin Pharmacol 20:849–854. doi: 10.1358/mf.1998.20.10.487540 PubMedCrossRefGoogle Scholar
  9. Jain NK, Patil CS, Kartasasmita RE, Decker M, Lehmann J, Kulkarni SK (2004) Pharmacological studies on nitro-naproxen (naproxen-2-nitroxyethylester). Drug Dev Res 61:66–78. doi: 10.1002/ddr.10337 CrossRefGoogle Scholar
  10. Koster R, Anderson M, De Beer EJ (1959) Acetic acid for analgesic screening. Fed Proc 18:412–426Google Scholar
  11. Laporte JR, Carne X, Vidal X, Moreno V, Juan J (1991) Upper gastrointestinal bleeding in relation to previous use of analgesics and non-steroidal anti-inflammatory drugs. Catalan countries study on upper gastrointestinal bleeding. Lancet 337(8733):85–89. doi: 10.1016/0140-6736(91)90744-A PubMedCrossRefGoogle Scholar
  12. Madhukar M, Sawraj S, Sharma PD (2010) Design, synthesis and evaluation of mutual prodrug of 4-biphenylacetic acid and quercetin tetramethyl ether (BPA-QTME) as gastrosparing NSAID. Eu J Med Chem 45:2591–2596. doi: 10.1016/j.ejmech.2010.02.047 CrossRefGoogle Scholar
  13. Menon B, Sharma PD (2009) Design, synthesis and evaluation of diclofenac-antioxidant mutual prodrugs as safer NSAIDs. Ind J Chem 48 B:1279–1287Google Scholar
  14. Moser P, Sallmann A, Wiesenberg I (1990) Synthesis and quantitative structure-activity relationships of diclofenac analogs. J Med Chem 33(9):2358–2368. doi: 10.1021/jm00171a008 PubMedCrossRefGoogle Scholar
  15. Neises B, Steglich W (1978) Simple method for the esterification of carboxylic acids. Angew Chem Int Ed 17:522–524. doi: 10.1002/anie.197805221 CrossRefGoogle Scholar
  16. Pérez Gutthann S, García Rodríguez LA, Raiford DS, Duque Oliart A, Ris Romeu J (1996) Nonsteroidal anti-inflammatory drugs and the risk of hospitalization for acute renal failure. Arch Inter Med 156(21):2433–2439. doi: 10.1001/archinte.1996.00440200041005 CrossRefGoogle Scholar
  17. Piacham T, Isarankura-Na-Ayudhya C, Nantasenamat C, Yainoy S, Ye L, Bülow L, Prachayasittikul V (2006) Metalloantibiotic Mn(II)-bacitracin complex mimicking manganese superoxide dismutase. Biochem and Biophy Res Commun 341:925–930. doi: 10.1016/j.bbrc.2006.01.045 CrossRefGoogle Scholar
  18. Sairam K, Rao CV, Dorababu M, Goel RK (2001) Prophylactic and curative effects of Bacopa monniera in gastric ulcer models: Abstract. Phytomed 8:423–430. doi: 10.1078/S0944-7113(04)70060-4 CrossRefGoogle Scholar
  19. Utley HG, Bernheim F, Hochstein P (1967) Effect of sulfhydryl reagents on peroxidation in microsomes. Arch Biochem Biophy 118:29–32. doi: 10.1016/0003-9861(67)90273-1 CrossRefGoogle Scholar
  20. Vane JR, Botting RM (1995) New insight into the mode of action of anti-inflammatory drugs. Inflamm Res 44:1–10. doi: 10.1007/BF01630479 PubMedCrossRefGoogle Scholar
  21. Winter CA, Risley EA, Nuss GW (1962) Carrageenan-induced edema in hind paw of the rat as an assay for anti inflammatory drugs. Proc Soc Exp Bio Med 111:544–547Google Scholar
  22. Wynne HA, Long A, Nicholson E, Ward A, Keir D (1998) Are altered pharmacokinetics of non-steroidal anti-inflammatory drugs (NSAIDs) a risk factor for gastrointestinal bleeding? Br J Clin Pharmacol 45(4):405–408. doi: 10.1046/j.1365-2125.1998.t01-1-00696.x PubMedCrossRefGoogle Scholar
  23. Yalkowsky SH, Morozowich W (1980) A physical chemical basis for the design of orally active prodrugs. In: Ariens EJ (ed) Drug design. Academic press, New York, pp 121–135Google Scholar
  24. Zuckner J (1986) International experience with diclofenac in rheumatoid arthritis. Am J Med 80(4B):39–42. doi: 10.1016/0002-9343(86)90078-1 PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2012

Authors and Affiliations

  • Kamal Shah
    • 1
    Email author
  • Sushant K. Shrivastava
    • 2
  • Pradeep Mishra
    • 1
  1. 1.Department of Pharmaceutical Chemistry, Institute of Pharmaceutical ResearchGLA UniversityMathuraIndia
  2. 2.Department of Pharmaceutics, Institute of TechnologyBanaras Hindu UniversityVaranasiIndia

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