Summary
In search for more potent, particularly less ulcerogenic gastritis that hopefully replace the universal NSAID “Diclofenac”, (2-[(2,6-di-chlorophenyl)amino]-phenylacetic acid, C.A.S. 15307-86-5), twelve new non-proteinogenic amino acid conjugates of the drug, namely that of sarcosine,β-alanine, D-leucine and D-phenylalanine, were synthesized and biologically screened for their anti-inflammatory, analgesic and ulcerogenic activity in rats.
“Diclofenac” amino acid esters (IIa-d), were synthesizedvia the corresponding HOSu or HOBt active esters. Alkaline hydrolysis (NaOH) followed by acidification (KHSO4) or thioamide formation (Lawsson's Reagent, C.A.S. 19172-47-5), afforded the corresponding free acids IIIa-d or the thioamides IVa-d respectively.
Interestingly, in contrary to the parent “Diclofenac”, the synthesized candidates (except IIId), were entirly nonulcerogenic in rats. Further, they considerably retained a generelized anti-phlogistic activity. The major “Diclofenac” irritating gastric side effect was thus eliminated.
Particularly, the sarcosine conjugate IIa and its thiomimic IVa exhibit promising therapeutic perspectives.
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Abo-Ghalia, M.H., Shalaby, A.M., El-Eraqi, W.I. et al. Synthesis and anti-phlogistic potency of some new non-proteinogenic amino acid conjugates of “Diclofenac”. Amino Acids 16, 425–440 (1999). https://doi.org/10.1007/BF01388181
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DOI: https://doi.org/10.1007/BF01388181