Synthesis and Structure-Activity Relationship Studies of Pyrazole-based Heterocycles as Antitumor Agents

Several 4‐cyano‐1,5‐diphenylpyrazoles attached to different heterocyclic ring systems at position 3 were synthesized starting from ethyl 4‐cyano‐1,5‐diphenyl‐1H‐pyrazole‐3‐carboxylate 1. The newly synthesized compounds were tested in vivo for their anti‐estrogenic effects and evaluated in vitro for...

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Bibliographic Details
Published in:Archiv der Pharmazie (Weinheim) 2010-07, Vol.343 (7), p.384-396
Main Authors: Farag, Ahmad M., Mayhoub, Abdelrahman S., Eldebss, Taha M. A., Amr, Abdel-Galil E., Ali, Korany A. K., Abdel-Hafez, Naglaa A., Abdulla, Mohamed M.
Format: Article
Language:English
Subjects:
1,2,4‐Triazoles
1,3,4‐Oxadiazoles
1,3,4‐Thiadiazole
1,5‐Diphenylpyrazoles
4-Oxadiazoles
4-Thiadiazole
4-Triazoles
5-Diphenylpyrazoles
Animals
Anti-estrogenic activity
Antineoplastic Agents - chemical synthesis
Antineoplastic Agents - pharmacology
Cell Line, Tumor
Drug Screening Assays, Antitumor
Estrogen Receptor Modulators - chemical synthesis
Estrogen Receptor Modulators - pharmacology
Female
Heterocyclic Compounds - chemical synthesis
Heterocyclic Compounds - pharmacology
Humans
Lethal Dose 50
Male
Mice
Nitriles - pharmacology
Pyrazoles - chemical synthesis
Pyrazoles - pharmacology
Rats
Rats, Sprague-Dawley
Structure-Activity Relationship
Triazoles - pharmacology
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Summary:Several 4‐cyano‐1,5‐diphenylpyrazoles attached to different heterocyclic ring systems at position 3 were synthesized starting from ethyl 4‐cyano‐1,5‐diphenyl‐1H‐pyrazole‐3‐carboxylate 1. The newly synthesized compounds were tested in vivo for their anti‐estrogenic effects and evaluated in vitro for their cytotoxic properties against estrogen‐dependent tumors. 3‐(5‐Mercapto‐1,3,4‐oxadiazole‐2‐yl)‐1,5‐diphenyl‐1H‐pyrazole‐4‐carbonitrile 13 revealed the highest cytotoxic activity with a GI50 value equal to 40 nM against the IGROVI ovarian tumor cell line. It also showed an anti‐estrogen activity 1.6 more effective than the reference drug, in addition to a high tolerable dose. 3‐(5‐(Methylthio)‐4‐phenyl‐4H‐1,2,4‐triazol‐3‐yl)‐1,5‐diphenyl‐1H‐pyrazole‐4‐carbonitrile 7 was found to have the highest anti‐estrogenic activity, while 1,5‐diphenyl‐3‐[5‐(phenylamino)‐1,3,4‐thiadiazol‐2‐yl]‐1H‐pyrazole‐4‐carbonitrile 11 showed the lowest activity. The oral LD50 values revealed that most of the tested compounds are relatively nontoxic.
ISSN:0365-6233
1521-4184
DOI:10.1002/ardp.200900176