ABSTRACT
A series of novel 3-(1H-indole-3-yl)-1H-pyrazole-5-carbohydrazide derivatives 4Ia-n, 4IIa-b and 6 were prepared by hydrazinolysis of ethyl 3-(1H-indole-3-yl)-1H-pyrazole-5-carboxylate with hydrazine hydrate in excellent yields. These new compounds were fully characterized by spectroscopic methods, and the important intermediates 3Ie, 3IIc and 3IId were further confirmed by X-ray crystallography. All the new compounds were evaluated for their cytotoxic activity against 4 human cancer cell lines by MTT method. Some of them exhibited more potent antiproliferative activity against HepG-2, BGC823 and BT474 cell lines than the positive drug 5-fluorourcail. Flow cytometry analysis showed that 4Ik and 4Il arrested the cell cycle at S phase.
Subject(s)
Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Hydrazines/chemistry , Hydrazines/pharmacology , Pyrazoles/chemistry , Pyrazoles/pharmacology , Antineoplastic Agents/chemical synthesis , Cell Cycle/drug effects , Cell Line, Tumor , Cell Proliferation/drug effects , Crystallography, X-Ray , Humans , Hydrazines/chemical synthesis , Models, Molecular , Neoplasms/drug therapy , Pyrazoles/chemical synthesis , Structure-Activity RelationshipABSTRACT
A series of novel compounds bearing a 3-(1H-indol-3-yl)pyrazole-5-carboxylic acid nucleus were synthesized. Analytical and spectral data confirmed the structures of the new compounds. The structures of the regioisomers in this series were determined by (1)H-NMR spectra. The title compounds were evaluated for their endothelin-1 antagonist activities. In the in vitro functional assay, compounds 23, 24, 28 and 29 exhibited significant efficacy at the concentration of 1 µg/mL, and compounds 5b, 5c, 26 and 28 were as potent as the positive control bosentan at high concentration. In the experiment to assess prevention of endothelin-1-induced sudden death in mice, compound 5b showed comparable activity to bosentan, and 30 was more potent than bosentan. The final compounds were also screened for antibacterial activity against four Gram-positive and -negative bacteria. Some of the tested compounds showed weak antibacterial activity.
Subject(s)
Anti-Bacterial Agents/chemical synthesis , Pyrazoles/chemical synthesis , Vasodilator Agents/chemical synthesis , Animals , Anti-Bacterial Agents/chemistry , Anti-Bacterial Agents/pharmacology , Aorta, Thoracic/drug effects , Aorta, Thoracic/metabolism , Death, Sudden/prevention & control , Endothelin-1/antagonists & inhibitors , Endothelin-1/pharmacology , Gram-Negative Bacteria/drug effects , Gram-Positive Bacteria/drug effects , In Vitro Techniques , Male , Mice , Mice, Inbred ICR , Microbial Sensitivity Tests , Molecular Structure , Pyrazoles/chemistry , Pyrazoles/pharmacology , Rats , Rats, Sprague-Dawley , Structure-Activity Relationship , Vasoconstriction/drug effects , Vasodilator Agents/chemistry , Vasodilator Agents/pharmacologyABSTRACT
The title compound, C(6)H(5)ClN(2)O(2), crystallizes with two independent mol-ecules in the asymmetric unit. Inter-molecular C-Hâ¯O hydrogen bonds stabilize the crystal structure.
