Synthesis and anti-phlogistic potency of some new non-proteinogenic amino acid conjugates of "Diclofenac".
In search for more potent, particularly less ulcerogenic gastritis that hopefully replace the universal NSAID "Diclofenac", (2-[(2,6-dichlorophenyl)amino]-phenylacetic acid, C.A.S. 15307-86-5), twelve new non-proteinogenic amino acid conjugates of the drug, namely that of sarcosine, beta-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 synthesized via 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 entirely nonulcerogenic in rats. Further, they considerably retained a generalized 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.
National Research Centre, Dokki, Cairo, Egypt.
M H
MH
Abo-Ghalia
A M
AM
Shalaby
W I
WI
el-Eraqi
H M
HM
Awad
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology / Q000633:toxicity; D004008:Diclofenac / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology / Q000633:toxicity; D051381:Rats; D012521:Sarcosine / Q000737:chemistry / Q000494:pharmacology; D015091:beta-Alanine / Q000737:chemistry / Q000494:pharmacology
D000894:Anti-Inflammatory Agents, Non-Steroidal; D015091:beta-Alanine; D004008:Diclofenac; D012521:Sarcosine