[New derivatives of triazino- and imidazoindole with hepatoprotective activity].
The effect of 30 indole derivatives (mainly condensed) containing a thio-carbamide fragment was investigated in rats using a model of carbontetrachloride-induced hepatitis and a model of partial hepatectomy (for some compounds). Among indoles, 1,2,4-triazino[5,6-b]- and [6,5-b]indole as well as imidazo[4,5-b]indole series the compounds, decreasing concentration of alanine aminotransferase, aspartate aminotransferase and total bilirubin in blood serum and reducing hexenal sleep duration were found. The compounds exceeding in this respect riboxine, potassium orotate and essentiale (used for comparison) and posessing sufficient therapeutic index were found. The correlation between biological activity and ionisation constants was observed for triazinoindole derivatives, while for some indices of liver state the correlation with ionisation constants and distribution coefficients in octanol/water system was found as well. High activity was most probable at pKa < or = 8. For aminoallcyl thioderivatives of triazinoindole the protective effect increased on substituting the aminogroup for hydrogen atom at 8-position, on increasing the side chain length from 2 to 3 methylene links and on replacing of acyclic aliphatic amines residues in a side chain by cyclic amines--pyrrolidine, N-methylpiperazine and morpholine rather than piperidine which increased toxicity. There was no correlation between hepatoprotective and antihypoxic activity while for actoprotectors the probability of liver protection was increased. The results indicate perspectives in searching new hepatoprotective agents among the indicated series of indole derivatives.
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D000818:Animals; D002252:Carbon Tetrachloride Poisoning / Q000188:drug therapy; D056486:Chemical and Drug Induced Liver Injury / Q000188:drug therapy*; D007211:Indoles / Q000737:chemistry / Q000627:therapeutic use*; D008099:Liver / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D051381:Rats; D013329:Structure-Activity Relationship; D014227:Triazines / Q000737:chemistry / Q000627:therapeutic use*
D007211:Indoles; D014227:Triazines